Index

Terms that begin with numbers transition state analogs, ADAM are indexed as if the number were 650-651 geometriclcombinatorial spelled out; e.g., "3D models" is Acetic acid search, 295 located as if it were spelled CML representation, 372 ADAMs, 652 "ThreeD models." Acetylcholine, 772 ADAPT, 53 cation-T bonding, 724-725 Adenosine deaminase inhibitors, conformationally restricted 717 structure-based design, analogs, 697-698 mass-spectrometric screening 437-438 muscarinic agonist analogs, for ligands to, 604 A-80987 143-144 transition-state analogs, structure-based design, 438, Acetylcholinesterase inhibitors, 750-752 439 718 X-ray crystallographic studies, A-306552,675 CoMFA study, 58-59 482 Absolv program, 389 pseudoirreversible, 772-774 S-Adenosyl-L-homocysteine, Absorption, distribution, metab- substrates from acetylcholine 733,740 olism, and excretion analogs, 697-698 S-Adenosyl-L-methionine, 733 (ADME) target of structure-based drug ADEPT suite, 225,226,237 as bottleneck in drug discov- design, 449-450 ADME studies, See Absorption, ery, 592 volume mapping, 140 distribution, metabolism, estimation systems, 389-390 X-ray crystallographic studies, and excretion (ADME) molecular modeling, 154-155 482 ADMET studies, See Absorption, Absorption, distribution, metab- N-Acetylcysteine distribution, metabolism, olism, excretion, and toxic- toxicological profile prediction, excretion, and toxicity ity (ADMET), 389 838,840 (ADMET) and druglikeness screening, 245 Acetylsalicylic acid (aspirin), ADP analogs, 763-764 and virtual screening filter 762-763 Adrenaline, 885,886 cascade, 267 Acquire database, 386 p-Adrenoreceptor antagonists, ABT-418,808-810 Actimomycin D See p-Blockers ABT-627,811-812 thermodynamics of binding to Afferent, 387 ABT-773,876 DNA, 183 Affinity calculation, 118-122 Academic databases, 387-388 Actinoplanes utahensis, 878 Affinity capillary electrophore- Acarbose, 849 Active Analog Approach, 58,60, sis-mass spectrometry, Accelrys databases, 384-385 639 599-600 Accord, 377,385 flow of information in, 146 Affinity chromatography-mass Accord Database Explorer, 385 and molecular modeling, 134, spectrometry, 598599 Acebutol 151 Affinity grids, 292-293 renal clearance, 38 and systematic search, Affinity labels, 756-759, ACE inhibitors, 718,881 144-145 760-764 asymmetric synthesis, 807,809 Active-site directed, irreversible Affinity NMR, 571 comparative molecular field inhibitors, 755 2-AG, 853 analysis, 151-153 Activity AG31 conformationally restricted binding affinity contrasted, structure-based design, peptidomimetics, 640 - 641 131-135 428-429 molecular modeling, 131, Activity-guided fractionation, AG85 132-133, 145 597 structure-based design, 428 multisubstrate analogs, Activity similarity, 255 AG331 746-748 Acyclovir, 717, 719, 756 structure-based design, receptor-relevant subspace, 204 Acyl halides 428-429 structure-based design, filtering from virtual screens, AG337 432-433 246 structure-based design, 428 901 Index

Alprenolol 6-Aminopenicillanic acid structure-based design, renal clearance, 38 (6-HA),869,870 431-432 Altracurium Aminopeptidases AG2037 lead for drugs, 856-858 transition state analog inhibi- structure-based design, AM1 wave function, 15, 102 tors, 652 431-432 AM404,854 8-Aminoquinolines, 888-889 Agenerase Arnaryllidaceue (snowdrops, daf- Amiodarone, 884,885 structure-based design, 440, fodils, etc.), 892 Amitriptyline, 692 441 Amastatin, 738 Ammi visnaga (toothpick plant), Agent, 398 AMBER energy function, 264, 883 Aggregate concept, in molecular 307-308 Amoxycillin, 869,870 modeling, 90 -91 performance in structure pre- AMP analogs, 764 AIDS, See HIV protease inhibi- diction, 315 Ampicillin, 869, 870 tors seeding experiments, 319 Amprenavir, 648,659 AIDS database, 386 AMBERIOPLS force field, 80, structure-based design, 440, AIMB, 255 81,103 ALADDIN, 259,363 in molecular modeling, 118 441 in molecular modeling, 111, American mandrake, drugs de- cu-Amylase 113 rived from, 865 X-ray crystallographic studies, Alaninates Amides 482 binding to chymotrypsin, 35 enzyme-mediated asymmetric P-Arnyloid Alanine racemase inhibitors, 717 bond formation, 804-805 X-ray crystallographic studies, Alcohol dehydrogenase exchange ratesltemperature 482 QSAU studies, 5 coefficients, in NMR, 512 Analog design, 687-689 Alcohols pharmacophore points, 249 alkyl chain homologation, 689, pharmacophore points, 249 Amines 699-704 QSAU studies, 27-29 pharmacophore points, 249, bioisosteric replacement and Alcuronium, 856,857 250 nonisosteric bioanalogs, Aldehydes Aminidine 689 - 694 filtering from virtual screens, pharmacophore points, 249 chain branching alteration, 246 Amino acid mimetics, 640 689 Aldose reductase inhibitors Amino acids fragments of lead molecule, novel lead identification, 321 chemical modification re- 689,707-710 target of structure-based drug agents, 755 interatomic distances varia- design, 447-449 chirality, 784 tion, 689, 710-712 Aldosterone, 746 classical resolution, 797 limitations of, 532 Alkyl amines conglomerate racemates, rigid or semirigid analogs, polarization energy, 173 802-803 689,694-699 protonation, 179-180 Aminoacyl-tRNA synthetases ring-position isomers, 689 Alkyl chain homologation ana- binding of alkyl groups to, 8 ring size changes, 689 logs, 699-704 y -Aminobutyric acid amino- stereochemistry alteration and Alkyl halides transferase (GABA-T) in- design of stereoisomers/geo- filtering from virtual screens, hibitors, 488, 718, 766-767 metric isomers, 689, 246 y -Aminobutyric acid (GABA), 704-707 Allinger force field, 80 766 substitution of aromatic ring Allosteric effectors analogs, 690 for saturated, or the con- of hemoglobin, 421-424 geometric isomer analogs, verse, 689 and lock-and-key hypothesis, 5 705-706 Anandamide. 853 N-Allylmorphine, 850 molecular modeling, 149 Anchor and grow algorithm, Almond program, 202 7-Aminocephalosporanic acid 294,296 Alogp, 390 (7-ACA),871,874 AND logical operator, 406 Alpha-amylase, 482 2-Amino-3-chlorobutanoic acid Androgen receptor N-Alpha-(2-naphthylsulfonylgly- nonclassical resolution, 803 X-ray crystallographic studies, cyl)-4-amidinophenylal[NA- Aminoglutethimide, 717 482 PAP] piperidide chromatographic separation, Angiotensin-converting enzyme structure-based design, 442, 792 (ACE), 650,881. See also 444 classical resolution, 798, 799 ACE inhibitors Index

active site molecular model- Arabinose binding protein Aspergillus alliaceus, 855 ing, 131,132-133 genetic algorithm study of Aspergillus nidlans, 878 target of structure-based drug docking, 88-89 Aspergillus terreus, 879 design, 432-433 Arachidonic acid, 762, 763 Asperlicin Angiotensin I, 432-433,746,881 Arecoline analogs, 693-694 fragment analogs, 708 Angiotensin 11, 432, 746, 881 Argatroban lead for drugs, 855-856 non-peptide antagonists, structure-based design, 442,444 Aspirin, 762-763,764 668-669,670 Arginase inhibitors, 736-737 Assay Explorer, 387 Anhydrides Arginine Association thermodynamics filtering from virtual screens, chemical modification re- drug-target binding, 170-171, 246 agents, 755 177-179 Anomalous Patterson maps, 477 Aromatase inhibitors, 717, 770 Asymmetric centers, 784,785 Antiasthma drugs Aromatic-aromatic interactions, Asymmetric synthesis, 784, natural products as leads, 286 804-820 883-886 Aromatics enzyme-mediated, 804-807 Antibacterial enzyme inhibitors, analogs based on substitution Asymmetric transformation 717 of aromatic for saturated crystallization-induced, Antibiotic drugs ring; or the converse, 798-799 natural products as leads, 699-704 Atenolol, 882 868-878 growth inhibition by, 38 renal clearance, 38 Antibiotic resistant pathogens, molecular comparisons, 139 Atom-atom mapping, 380,398 7 70 ArrayExpress, 345 Atom-centered point charges, Anticancer drugs Artabotrys uncinatus, 887 101-102 enzyme inhibitors, 717, 718 Arteether, 887 Atomic counts, 54 molecular modeling, 151 Artemether, 887-888 Atom list, 398 natural products as leads, Artemisia annua (sweet worm- Atom-pair interaction potentials, 858-868 wood), 886,888 120 Anticoagulant protein C Artemisinin, 849,886-888 Atom stereochemistry, 365,398 X-ray crystallographic studies, Artificial intelligence, 398 Atom-type E-State index, 26 482 Artificial neural networks Atorvastatin, 744, 880 Anticoagulants, 882-883 for druglikeness screening, ATP analogs, 763-764,765 Antifolate targets 247-248,250 Hf ,KC-ATPase inhibitors, 718 structure-based design, in molecular modeling, 126 Na+,K+-ATPaseinhibitors, 718 425-432 in QSAR, 53,62,67 Atracurium, 857,859 Antifungal enzyme inhibitors, for structural genomics study, Atrasentan (ABT-6271,811-812 717 353 Atrial natriuretic factor, 650 Antiparasitic drugs Arylsulfonamidophenethano- Atrolactate, 762 natural products as leads, lamine analogs, 703 Atropine 886-891 p-Arylthio cinnamide antago- lead for drugs, 851 Antiprotozoal enzyme inhibi- nists, 566-567 Augmentin, 869 tors, 717 ASCII (American Standard Code Aura-Mol, 388 Antisickling agents, 419-421 for Information Exchange), AUSPYX, 387 Antiviral enzyme inhibitors, 717 398 AutoDock Aparnin Ascomycin affinity grids, 293 molecular modeling, 124 binding to FKBP, 552, explicit water molecules, 303 AP descriptors, 55, 56 553-554 flexible ligands, 263 Apex, 256,387 Asinex catalog, 385 Lamarckian genetic algo- Apex-3D, 60 Aspartate transcarbamoylase rithm, 299 Application tier, 392,398,406 (ATCase) inhibitors, Monte Carlo simulated an- Aquaporin 1 743-744 nealing, 297 X-ray crystallographic studies, Aspartic acid protein flexibility, 301 482 chemical modification re- Automap, 398 Aqueous solubility agents, 755 Available Chemicals Directory and structure-based design, Aspartic peptidase inhibitors (ACD), 385,386 408 transition state analogs, virtual screening application, Arabidopsis thaliana 647-649 254 genome sequencing, 344 virtual screening, 315 Avermectins, 891,892 Index

Azathioprine, 717 Bezafibrate, 422 BIRB-796 Azithromycin, 848,849, BIBP 3226,670,673 structure-based design, 875-876 BIBR 953 458-459 Aztreonam, 873-874 structure-based design, 443, Bisubstrate analog enzyme in- 448 hibitors, 741-742 Babel, 372 BIBR 1048 Bitset, 399 Baccatin 11,863 structure-based design, 442, BLAST (Basic Local Alignment Backtracking, 382,399 443 Search Tool), 347 in virtual screening, 67 BIBU52,213 BLEEP potential, 312 Bacterial luminescence Bifenthrin, 41, 42 performance in structure pre- inhibition by ROH, 27 Binary data, 373,399 diction, 314 Bacterial natural products, 848, Binary QSAR, 4 BLOB (Binary Large Object) 893 Binding afiinity, 286 data type, 399 Bacteriorhodopsin activity contrasted, 131-135 Blood substitutes electron cryomicroscopy, 612 calculation, 118- 122 structure-based design, 424 homology with GPCRs, 123, Binding constant, 286 BMS-193884,674,676 150 Binding property classes, 192 BMS-247550,864,865 Barnard Chemical Information, Binding site models, 130 Bohm scoring function, 264 388 Bioactivity databases, 386 Boltzmann law, 93,310311 Bcl-xL Bioafiinity screening Boltzmann probability, 94 target of spin-label NMR by electrospray FTICR MS, Boltzmann weighted average, screening, 573-574 601-603 97,98 BCUT descriptors Bioavailability, 716 Bond stereochemistry, 365, defined, 399 BioCatalysis database, 384 399-400 estimation systems, 388 Biochemical force fields, 175-176 Born-Oppenheimer approxima- for molecular similarityldiver- Bioinformatics, 333-337 tion, 79 sity methods, 193-194, databases, tools, and applica- Born-Oppenheimer surface, 85 203-204 tions, 345-349 Bothrops jarma (pit viper), 881 with pharmacophore finger- defined, 399 Bovine liver DHFR, QSAR inhi- prints, 223-224 and functional genomics, bition studies, 34 for target class-focused ap- 338340 Bovine pancreatic trypsin inhibi- proaches, 228-229,232-233 future developments, 354 tor BCX 1812 and sequences, 364 long range electrostatic ef- . structure-based design, 452 standardization, 337 fects, 177 BDE index, 11 and structural genomics, Bradykin, 746,881 Beilstein Database, 362,385 352-354 targeted library design, 69, 70 Beilstein Online, 385 for target discovery, 335, BRIDGE, 113 Benign prostatic hypertrophy 338-345 BRN (Beilstein Registry Num- expression probabilities, 343 Bioinformatics knowledge ber), 378, 400 Benzamidines model, 349-352 Bromoaspirin, 763 inhibitors of trypsin, 120 Bioisosteric replacement ana- Bromobutide, 42 Benzene logs, 689-694 Bromperidol electron density, 135 Biological data, 399 HIV protease inhibitor, 111, intermolecular interactions, Biological evaluation 112 174 in structure-based design, 419 Bryostatin-1, 868,869 Benziodarone, 884 BioScreen NPISC, 385 Bufuralol Benzomorphans, 850 BIOSTER database, 202,384 renal clearance, 38 Benzopyran Biosterism, 689-690 Bugula neritina, 868 enzyme-mediated oxidation, Biotin Building block hypothesis, 88 806 genetic algorithm study of Bupivacaine hydrochloride, 805, Benzylpenicillin, 868,870 docking to streptavidin, 89 806 (R)S-Benzylsuccinic acid, 746 interaction with streptavidin, classical resolution, 795, 796 Bestatin, 652, 654, 728 181-183 Buprenorphine, 850-851 p-Blockers, 881-882 Biotransformations database, 384 Business rules, 378,400,403 enantiomers, 786 Biphenyls BW12C nonrenal clearance, 39 privileged structures, 252 antisickling agent, 419-420 renal clearance, 38 Biphenyl tetrazole, 231 BW1476U89,742-743 Index

CACTVS, 254 Carboxypeptidase A Cathepsin D Calabash curare, 856 similarity of active site to combinatorial docking studies, Calcineurin A ACE, 433,746-747 318 X-ray crystallographic studies, Carboxypeptidase inhibitors non-peptide inhibitors, 227 483 conformational changes on Cathepsin K Cambridge Crystallographic Da- binding, 261 transition state analog inhibi- tabase, 110 genetic algorithm study of ac- tors, 654-655, 656 Cambridge Structural Database, tive site, 89 Cation-P interactions, 286, 313 354,387 molecular modeling, 116 enzyme inhibitors, 724-725 X-ray crystallography applica- Cardiovascular drugs CATS descriptors, 192 tion, 479 natural products as leads, CAVEAT, 111,113 CAMP 878-883 CAVITY, 106-107,108 molecular property visualiza- CART, 67 tion, 137 CBS reduction, 814 D-Camphor Cascade clustering cDNA clone libraries, 341-342 connection table, 367 with molecular similarityldi- cDNA microarray chips, tabular molecular file formats, versity methods, 205 344-345 370-371 CASETox, 246 Cefaclor, 872 CAMP phosphodiesterase I1 in- CAS Numbers, 378,400 Cefadroxil, 872 hibitors CAS ONLINE, 361 Cefetamet pivoxil, 849 molecular modeling, 130 similarity searching, 383 Cefozopran, 849 Camptotheca acuminata, 860 Caspase-1 inhibitors Cefpimizole, 849 Camptothecin target of structure-based drug Cefsulodin, 849 drugs derived from, 860-861 design, 443 Ceftazidime, 872,873 Candoxatril, 815,818 transition state analogs, 655 Ceftizoxime, 872,873 Cannabinoids Caspase-3 inhibitors Ceftriaxone, 872,873 lead for drugs, 852-854 transition state analogs, 655 Cefuroxime, 872,873 Cannabis sativa, 852 Caspase-7 inhibitors Cell-based partitioning methods, Canonical numbering, 378,400 transition state analogs, 655 203 Capillary electrophoresis CASP experiment (Critical As- CellCept for enantiomer separation, 787 sessment of techniques for structure-based design, Capsaicin, 854 protein Structure Predic- 446-447 Captopril, 646,650,746-747, tion), 123,353 Central Library, 378,387 881 Caspofungin, 848,878 Central nervous system (CNS) asymmetric synthesis, 807, drugs, See CNS drugs CASREACT, 385 809 Cephacetrile, 871,874 CAS Registry, 363,385 structure-based design, Cephalexin, 871-872 Catalyst (program), 259 432-433,434 Cephaloglycin, 871-872 Carbamates 3D shape-based searching, Cephaloridine, 871,872 pharmacophore points, 249 199,201 Cephalosporin C, 870471,874 Carbenin, 849 for novel lead identification, Cephalosporins, 717,870-871 Carbo index, 202 321 preventing bacterial degrada- Carbonic anhydrase inhibitors, Catalyst/Hip/Hop, 60 tion, 718 718 Catalyst/Hypo, 60 Cephalosporium acremonium, 4-fluorobenzenesulfonamide Catechol methyltransferase 870 binding to, 538 X-ray crystallographic studies, Cephalothin, 871,874 molecular modeling, 120 484 Cephamandole, 872,873 virtual screening for, 316 CATH, 353 Cephapririn, 871, 874 Carbonic anhydrase I1 inhibi- X-ray crystallography applica- Cephradine, 872 tors, 718 tion, 494 Cerivastatin, 880 novel lead identification by Catharanthus roseus, vinca alka- Cetirizine, 783 virtual screening, 320 loids from, 858 Cetirizine dihydrochloride X-ray crystallographic studies, Catharanthus (vinca) alkaloids, chromatographic separation, 483-484 858-860 790-791 Carboxylic acids Cathepsin B cGMP pharmacophore points, 249 transition state analog inhibi- molecular property visualiza- privileged structures, 252 tors, 654 tion, 137 Index

CGS 27023 Chemical libraries, See Libraries Chiral catalysts, 814-820 structure-based design, 444, Chemical Products Index, Chiral centers, 783-785 446 391-392 Chiral derivatizing agents, 788 Chain branching alteration ana- Chemical property estimation Chiral flags, 365,366 logs, 699-704 systems, 388390 Chirality, 781-787,820-821 Chapman databases, 387 Chemical reactions, 366 asymmetric synthesis, Charge-charge interactions, 82 searching, 379 -384 804-820 Charge-coupled devices (CCDs) Chemical representation, chromatographic separations, for electron cryomicroscopy, 363-373 787-793 623 Chemical shift, in NMR, 511, classical resolution, 793-799 for X-ray crystallography, 474 512 enzyme-mediated asymmetric Charge-dipole interactions, 82 changes on binding, 536-537 synthesis, 804-807 Charge parameterization, perturbations as aid in NMR nonclassical resolution, 101-102 screening, 562-568 799-804 Charge state determination Chemical-shift mapping, in Chiral pool, 807-810 NMR spectroscopy for, 526 NMR, 543-545 Charge transfer energy, 173 Chemical similarity, 382 Chiral reagent, 813-814 CHARMM, 298,299,307-308 Chemical space, 244, 383,400 Chiral stationary phase, in molecular modeling, 118, exploring with molecular simi- 787-788,790-791 126 larity/diversity methods, Chlopromazine, 692 CheD, 387 188, 191 Chloramphenicol, 870 ChemBase, 362 reduction by virtual screening, molecular modeling, 150 CHEMCATS, 385 244-245 4-Chloro-l,3-benzenediol CHEMDBS3D, 260,363 Chemical Structure Association, allergenicity prediction, 834 ChemDraw, 362 360 Chloromethyl ketones ChemEnlighten, 387 Chemical structures protease inhibitors, 761-762 ChemExplorer, 384 file conversion, 372-373 p-Chlorophenylalanine ChemFinder for Word, 384,388 searching, 379 -384 classical resolution by crystal- ChemFolder, 388 Chemical suppliers searching, lization, 798-799, 800 Chemical Abstracts (CAS) regis- 384 Chloroquine, 889,890 try file, 50 CHEM-INFO, 360 Chlortetracycline, 870 Chemical Abstracts Service da- ChemInform, 386 Cholchicine tabases, 254,361,385 Cheminformatics, 359,400 toxicological profile prediction, Chemical business rules, 378, Cheminformatics Glossary, 360 841,842 403 ChemPort program, 385 Cholecystokinin, 855 Chemical information comput- Chemscape, 387 X-ray crystallographic studies, ing systems, 357-363 ChemScore 484 chemical property estimation consensus scoring, 266 Chorismate mutase inhibitors systems, 388-390 empirical scoring, 310 transition state analogs, chemical representation, ChemSpace, 199 753-754 363-373 ChemText, 362 Chromatographic separation databases, 384-388 ChemWindow, 388 of chiral molecules, 787-793 data warehouses and data Chem-X, 60, 111 Chromobacterium violactum, marts, 390393,402-403 CheflChemDiverse 873 future developments, 393-397 3D pharmacophores, 195-196, Chromosomes glossary of terms used, 206 in genetic algorithms, 87 397-412 optimization approach, 217 Chymotrypsin inhibitors registering chemical informa- and property-based design, affinity labels, 761, 762 tion, 377-379 234 molecular modeling, 118 searching chemical structures1 Cherry picking, combinatorial QSAR studies, 5, 35-36 reactions, 379-384 libraries, 216-217,237 CICLOPS, 223 storing chemical information, Chesire, 378,387 Cilazapril 373-377 Chicken liver DHFR, QSAR in- asymmetric synthesis, 807, Chemical information manage- hibition studies, 31-32 809 ment databases, 384 Chilies, capsaicin in, 854 Cilofungin, 877 Chemical information manage- Chime, 369,371,387 Cinchona bark, quinine from, ment systems, 384 Chiral auxiliary, 810-813 888 Index

CIP (Cahn-Ingold-Prelog) stere- Coagulation factor 10 Comparative binding energy ochemistry, 365,400 X-ray crystallographic studies, analysis (COMBINE), 53 Cisplatin 484 and docking methods, vindesine with, 860 COBRA, 255 304-305 cisltrans stereochemistry, 399 R-Cocaine Comparative molecular field Clarithromycin, 849,874, dopamine transporter inhibi- analysis (CoMFA), 53-54 875-876 tor, 268 assessment of predictability, Classical resolution, of chid Codeine, 849,850 151-153 molecules, 793-799 Coformycin, 750-752 3D, 58-60 Clavulanic acid, 718,869,870 Cognex and docking methods, 304 Cleaning and transforming data, structure-based design, 449 field mapping, 107 400 Colforsin daropate, 849 molecular field descriptors, Clenbuterol Collagenase 56-57 chromatographic separation, NMR binding studies, 555, and molecular modeling, 138, 787,788 556 147 Client-server architecture, target of structure-based drug 400-401 design, 443 Comparative quantitative struc- Clipping, 378,401 CombiBUILD, 227 ture-activity relationships Clique search techniques, 262 CombiChem Package, 386 database development,- 39 CLOB (Character Large Object) CombiDOCK, 217,227 database mining for models, data type, 401 combinatorial docking, 318 39-41 Clofibric acid CombiLibMaker, 378,387 Competitive inhibitors, 728-729 antisickling agent, 421, 422 Combinatorial chemistry, 283, Complementarity, 134 CLOGP, 18,389 358,591-592 Comprehensive Medicinal Clog P, 17-18,36 defined, 401 Chemistry database, 379, Cloning, 127 and molecular modeling, 155 386 cDNA clone libraries, 341-342 and natural product screen- Computational Chemistry List, Clotrimazole, 717 ing, 848 360 Clustering methods, 379,401 Combinatorial chemistry data- Computational protein-ligand for combinatorial library de- bases, 387 docking techniques, sign, 220 Combinatorial docking, 317318 262-264 in molecular modeling, 90-91 Combinatorial libraries, 214 Computing technologies, with molecular similarityldi- comparisons, 221-223 334-335, 337. See also versity methods, 205 design for molecular similarity Chemical information com- CML (Chemical Markup Lan- methods, 190,214-228 puting systems guage), 371372,401,405, encoding and identification COMSiA, 53,60 412 with mass spectrometry, CONCORD, 363,366,387,401 CNS drugs 596-597 3D coordinate generation, 267 complementarity, 134 integration, 224-225 3D descriptors, 55, 110 natural products as leads, LC-MS purification, 592-594 virtual screening application, 849-856 optimization, 217-221 254 pharmacophore point filters, peptidomimetics, 657 Concordance, 390,401 250 screening for ligands to two Conformational analysis polar surface area, 245 receptors simultaneously, in molecular modeling, 87, CNS program, 478 601-602 93-94 Coagulation factor 2 structure-based design, NMR spectroscopy for, X-ray crystallographic studies, 225-228 525-526 484-485 structure/purity conhation and systematic search, 89-93 Coagulation factor 7 with mass spectrometry, Conformational clustering, X-ray crystallographic studies, 594-596 92-93 485 with virtual screening, 317 Conformational flexibility, 288 Coagulation factor 7a S,S-Combretadioxolane, 816, Conformationally restricted ana- X-ray crystallographic studies, 819 logs, 694-699 485-486 Combretastatin A-4,816,819 Conformationally restricted pep- Coagulation factor 9 CoMFA, See Comparative molec- tides, 636-643 X-ray crystallographic studies, ular field analysis Conformational mimicry, 486 Compactin, 744,879 140-142 Index

Conformational mimicry index, Cox-1 inhibitors, 718 Cyclosporin, 848 142 X-ray crystallographic studies, molecular modeling, 106 Conglomerate racemates, 486 NMR spectroscopic binding 799-800,801,802-803 COX-2 inhibitors, 718 studies, 539 Connection tables, 365-368,371, mass-spectrometric binding Cyclosporin A 401 assay screening, 604 binding to FKBP, 552-553 file conversion, 372373 seeding experiments, 319 y -Cystathionase inhibitors, ISIS database, 376 X-ray crystallographic studies, 719-720 Connectivity, See Molecular con- 486 Cysteine nectivity CP-96,345, 670,672 chemical modification re- o -Conotoxins C-QSAR database, 39 agents, 755 Cysteine peptidase inhibitors lead for drugs, 851-852 Crambin transition state analogs, NMR spectroscopy, 518-523 molecular modeling, 124 652-655 ConQuest search program, 387 Crixivan Conscore constraint score, 218 Cysteine protease inhibitors structure-based design, Consensus scoring, 265-266, affinity labels, 762 438-439 291,319-320 Cytochrome P450 and molecular modeling, CROSS-BOW, 361 homology modeling, 123 117-118 Crossfire Beilstein, 385 Cytochrome P450 reductase Consistent force fields, 102 Cross-linked enzyme crystals, X-ray crystallographic studies, Constrained minimization, 804 486 143-144 Crosslinking agents, 424-425 Cytosine arabinoside, 717, Contact matrix, 125-127 Cross validation, 57, 64 867-868 Contignasterol, 886 Cryoprobes CONTRAST, 361 in NMR screening, 577 D2163,804,806 Conus magus, conotoxins from, in NMR spectroscopy, 515 Daemon, 392,402 851 Cryptotheca cripta, 867 Daffodils, drugs derived from, Convertases Crystallization 892 homology modeling, 123 for asymmetric transforma- Dalfopristin, 876-877 CONVERTER, 366,402 tion of enantiomers, Spiro-DAMP, 696 CoQSAR, See Comparative 798-799 4-DAMP quantitative structure-adiv- for enhancing chromato- semirigid analogs, 695-696 ity relationships graphic separation of enan- Daptomycin, 848 CORINA, 366,402 tiomers, 792-793 DARWIN, 299 3D coordinate generation, 267 in nonclassical resolution, explicit water molecules, 303 3D descriptors, 55 799-804 Databases virtual screening application, CScore, 117 for bioinformatics, 345349 254 Curare cDNA microarray chips, 345 Cosine coefficient, 68 lead for drugs, 856-858 chemical information manage- COSMIC force field, 80 Cyclic lactarns ment, 384 Coulomb's law, 80,82,285 conformationally restricted commercial systems for drug- and dielectric problem, 83 peptidomimetics, 640-642 sized molecules, 384387 Coumarin, 882 Cyclic protease inhibitors, 636 comparative QSAR, 39-41 Counting schemes Cyclin-dependent kinase 2 comparing expressed sequence in druglikeness screening, (CDK2) tags with, 342 245-246 H717 inhibitor pharmaco- history of, 360-363 Coupling constants, in NMR, phore, 253 knowledge discovery in, 511,512 Cyclo(Gly6) 393395 changes on binding, 536-537 genetic algorithm exploration natural products, 387,597 for conformational analysis, 525 of conformational space, 88 for pharmacophore screening, COUSIN, 361,373,387 Cycloheptadecane 254-255 and combinatorial library in- potential smoothing study, 86 proprietary and academic, tegration, 224 Cyclooxygenase 112 inhibitors, 387-388 Covalent bonds, 6,170 See COX-1 inhibitors; sequence and 3D structure, Covalently binding enzyme in- COX-2 inhibitors 387 hibitors, 720, 754-756 Cyclophilin, 552 storing chemical information inactivation of, 756-760 D-Cycloserine, 717, 719 in, 373-377 Index

for X-ray crystallography, Diastereomers, 784 X-ray crystallographic studies, 478-479 chromatographic separation, 486 Database tier, 393,403,407 788 Dihydropteroate synthetase in- Data cartridges, 395,402 Dice coefficient, 68 hibitors, 717 Data compression, 402 Dicoumarol, 882 X-ray crystallographic studies, Data dictionary table, 375 Dictionary of Natural Products, 486 Data marts, 391393,402 597 1,4-Dihydropyridines Data mining, 402,410,411,412 Dideoxyinosine, 717 chromatographic separation, future prospects, 394-395 Dielectric problem, 83-84 788,789 with QSAR, 66-67 Dienestrol, 706-707 Dihydroquinine, 889 Data warehouses, 390-393, Diethylstilbestrol Dihydrotestosterone, 36, 768 402-403 stereoisomer analogs, 706-707 Diller-Merz rapid docking ap- Dative bonds, 170,365 Diffusion-filtered NMR screen- proach, 292,295 Daunomycin ing, 570-571 assessment, 303 thermodynamics of binding to a-Difluoromethylornithine, 717 combinatorial docking, 317 DNA, 183 Digital Northern, 342 Diltiazem DayCart, 386 Dihydroartemisinin, 887 nonclassical resolution, 803, DayCGI, 386 Dihydrofolate reductase inhibi- 805 Daylight Chemical Information tors, 545, 717 Dimension tables, 390,403 Systems databases chemical-shift mapping of N,N-Dimethyldopamine descriptors, 192 binding, 545 alkyl chain homologation ana- in virtual screening, 254 comparative molecular field logs, 701 10-Deacetylbaccatin 11,803 analysis, 153 bioisosteric analogs, 690, 692 Decamethonium, 58 genetic algorithm study of ac- semirigid analogs, 695 fragment analogs, 708-710 tive site, 89 A6,,,,-DimethylheptylTHC, 852 lead for drugs, 856-858 genetic algorithm study of Dimethyl sulfoxide (DMSO) Deceptive fitness functions, 88 docking, 88-89 force field models for, 176 Decision support systems, 403 interaction with methotrex- Dimethyltubocurarine, 857 Decision tree approach, 247-248 ate, 120 Diphenylmethane, 231 Deconvolution, 401 interaction with tri- privileged structures, 252 Deduplication, 378,403 methoprim, 151,183 2,3-Diphosphoglycerate Dehydroalantolactone interaction with trimetrexate, (2,3-DPG),104,421 allergenicity prediction, 836 531,557459 2,3-Diphosphoglycerate Demexiptiline, 692-693 mass-spectrometric binding (2,3-DPG)analogs, 103, 104 DENDRAL, 393 assay screening, 604 Dipolar electrostatic forces, 172 De novo design, 113 molecular modeling, 114, 115, Dipole-dipole interactions, 6,82 (R)-Deoxycoformycin, 750-752 116,147,151 Dipole-induced dipole interac- (S)-Deoxycoformycin, 751 QSAR studies, 5 tions, 173 DEREK, 246 QSAR studies of inhibition by Directed tweak algorithm, 260 Dement Information databases, diamino, 5Y, 6-Z-quinazo- Directionality, 140 386 lines, 34-35 DISCO, 58,60,256 Dement Selection database, 386 QSAR studies of inhibition by and molecular modeling, 147 Dement World Drug Index diamino-5X-benzyl pyrimi- Discodermolide (WDI), 379, 386, 387 dines, 39 genotoxicity prediction, 843 Dement World Patents Index QSAR studies of inhibition by Disintegrins, 652 (WF'I), 386 triazines, 31-33 Disoxaril 10-Desacetylbaccatin111,863 target of structure-based drug structure-based design, Descriptor pharmacophores, design, 425-426 454-455 60 - 63 volume mapping, 140 Dispersive interactions, 82, 174. Design in Receptor (DiR) ap- X-ray crystallographic studies, See also van der Wads proach, 236 486 forces DHFR, See Dihydrofolate reduc- Dihydromuscimol, 690 Dissimilarity approaches, tase Dihydroorotase 189-190,206-208 Diamino, 5Y, 6-Z-quinazolines transition state analogs, 752 Dissociation constant, 286 QSAR studies of DHFR inhibi- Dihydroorotate dehydrogenase Distamycin tion, 34-35 inhibitors binding perturbations, 544 Index

Distance geometry methods DNA topoisomerase 1 protein-ligand docking soft- in molecular modeling, 126, X-ray crystallographic studies, ware, 261 142,147 487 and QSAR, 304-305 in QSAR, 60 Docetaxel, 849,863 searching configuration and in virtual screening, 263 DOCK conformation space, Distance geometry QSAR tech- anchor and grow algorithm, 294-300 nique, 53 296 seeding experiments, 318-319 Distance matrix, 135 assessment, 303,304 special aspects, 300-306 Distance measures combinatorial docking, 318 in structure-based virtual molecular modeling, 135-137 consensus scoring, 266 screening, 260-267 molecular similarityldiversity empirical scoring, 310 as virtual screening tool, methods, 201-202 force field-based scoring, 308 266-267 Distance range matrix, 135-136 water's role, 302-303, force-field scoring, 264 Dithromycin, 875 313-314 geometriclcombinatorial DiverseSolutions, 387 Docking problem, 289 for molecular similarityldiver- search, 295 DockIT, 261 sity methods, 193-194, ligand handling, 293 Dockvision, 261 203-204 molecular modeling, 112, 113, Dolabella auricularia, 868 Diversity analysis, 358 115,116 Dolastatin-10, 868,869 Diversity methods, See Molecu- molecular modeling of small DoMCoSAR approach, 305 lar similarityldiversity cavity, 106, 107 Donepezil methods penalty terms, 313 structure-based design, 449 Diversity-property derived performance in structure pre- L-Dopa, 785 (DPD) method, 201,203 diction, 314 analogs, 690 Dixon plots, 731-732 protein and receptor model- Dopamine D,L descriptors, for chiral mole- ing, 267 semirigid analogs, 697 cules, 783 protein flexibility, 301 Dopamine-transporter inhibitors DMB-323 receptor representation in, pharmacophore model, 256, NMR binding studies with 291 258 HIV protease, 560-562 rigid docking, 262-263 virtual screening, 267-269, DMHB sampling/scoring methods 270 structure-based design, 424 used, 261 D-Optimal designs, 65-66 DMP 450,659 seeding experiments, 319 Dose-response curves, 8 structure-based design, with site-based pharmaco- Dothiepin, 692-693 438-439 phores, 236 Doxepin, 692-693 DNA DOCK4.0 DragHome method, 305 molecular modeling, 154 PMF scoring, 265 DRAGON, 388-389 NMR structural determina- weak inhibitors, 319 DREAM++, 318 tion, 535 Dockcrunch project, 317 Drill-down, 391,403 noncovalent bonds in, 170 Docking methods. See also Scor- Dronabinol, 849 supercoiling modeling, 95 ing functions; various dock- Drug databases, 385-386. See synthesis inhibition by phe- ing programs; Virtual also Databases nols, 40 screening Drug Data Report, 379,386 DNA-binding drugs assessment, 303-304 Drug development, 509-510 chemical-shift mapping of basic concepts, 289-290 serial design costs, 359 binding to, 544-545 combinatorial, 317-318 Druglikeness screening. See also molecular modeling, 116 flexible ligands, 293-294,322 Lipinski's "rule of 5" NMR spectroscopy, 547-552 and homology modeling, molecular similarity/diversity thermodynamics of binding, 305-306 methods, 191 183 and molecular modeling, similarity searching, 383 DNA gyrase inhibitors 113-118 virtual screening, 245-250 novel lead identification, 321 and molecular size, 312313 Drug-receptor complexes, DNA helicase pcra NOE docking in NMR, 170-179 X-ray crystallographic studies, 545-546 low energy state of, 5 487 penalty terms, 313 Drug resistance DNA polymerase inhibitors, 342, protein flexibility, 300-302, antibiotic resistant pathogens, 717 322 770 Index

essential pathways versus sin- Electronic parameters Encryption, 403 gle enzyme inhibitor, 495 in QSAR, 11-15,50 Endorphins, 634,850-851 Drugscore function, 311,312 Electron lenses, 612 model receptor site, 149 assessment. 303 Electron probability distribu- Endothelin performance in structure pre- tion, 101 antagonists, 211, 672-674, diction, 314 Electron-topological matrix of 675,676 seeding experiments, 319 congruence, 147 conformationally restricted in virtual screening, 315 Electron-withdrawing substitu- peptidomimetics, 637, 639 Drug screening, See Screening ents, 11-15 NMR spectroscopy, 523-524, Drug-target binding forces, growth inhibition by, 41 526-527 170-171 Electrospray FTICR mass spec- ENERGI approach, 127 association thermodynamics, trometry, 601-603 Energy driven/stochastic search 170-171,177-179 Electrostatic interactions, strategies, 292,296-2300 energy components for inter- 171-172,285 Energy of association, 177 molecular noncovalent in- charge parameterization, English yew, paclitaxel from, teractions, 171-174 101-102 861-862 example drug-receptor inter- and docking scoring, 308 Enkephalins, 634,850-851 actions, 181-183 enzyme inhibitors, 721, 723 conformationally restricted free energy calculation, long range, 177 peptidomimetics, 129, 637, 180-181 molecular modeling, 81-85, 639 molecular mechanics force 108-110,140 model receptor site, 149 fields, 174-177 and molecular property visual- Ensemble, 94 Drug targets ization, 137 Enthalpy of association and bioinformatics, 351-352 and QSAR, 6-7,52 drug-receptor complexes, estimated number of, 50 Electrotopological indices, 4 170-171 x-ray crystallography of pub- Elimination algorithms, 207 Entoviruses lished structures, 482-493 EMBL Nucleotide Sequence Da- target of structure-based drug DYLOMMS, 107 tabase, 335 design, 454-456 Embryo tail defects, 40 Entrainment, 802 E. Coli EMD 122946,676 Entropy, 94 mutagenicity prediction, 829 Empirical scoring, 264, 307, Entropy of association Eadie-Hofstee plot, 727, 729, 731 308-310 drug-receptor complexes, ECEPP force field, 118 Enalapril, 650,747,881 170-171 Echinocandins, 877-878 asymmetric synthesis, 807, Enumerated structure, 368 Ecteinascidia turbinata, 868 809 Enumeration, 401,403 Ecteinascidin-743, 848, 867-868 conformationally restricted Enzyme-induced inactivators, ECTL (Extracting, Cleaning, peptidomimetics, 640-641 756 Transforming, and Loading) Enalaprilat, 650, 747 Enzyme-inhibitor complexes, data, 377-379,403 conformationally restricted 721-722 Edman sequencing, 518 peptidomimetics, 640-641 Enzyme inhibitors, 715-720. See Edrophonium, 58 Enantiomeric excess, 784 also specific Enzymes Efaproxaril (RSR-13),422 enrichment by crystallization, affinity labels, 756-759, Eflornithine, 768, 769 800-802 760-764 Eigenvector following method, Enantiomers, 365, 366. See also design of covalently binding, 292,301 Chirality 720, 754-756 Einstein-Sutherland equation, 24 with agonist-antagonist prop- design of noncovalently bind- Elan, 387 erties at same receptor, 705 ing, 720-754 Electron cryomicroscopy, chromatographic separations, examples used in disease 611-628 787-793 treatment, 717 image processing and 3D re- defined, 783-785 ground-state analogs, 720, construction, 624-628 Enantioselective metabolism, 740 -741 image selection and prepro- 786-787 inactivation of covalently cessing, 623-624 Enantioselectivity, 784 binding, 756-760 three-dimensional, 615-616 Encoding mechanism-based, 759-760, Electron-donating substituents, and genetic algorithm, 88 764-771 12-15 natural products with mass multisubstrate analogs, 720, growth inhibition by, 41 spectrometry, 596-597 741-748 Index

Enzyme inhibitors (Continued) Etodolac FeatureTrees, 316,321 pseudoirreversible, 771-774 classical resolution, 796-797 Fibonacci search method, 11 rapid, reversible, 720, Etoposide, 717,867 Fibrinogen 728-734 Etorphine, 851 virtual screening studies, slow-, tight-, and slow-tight- Euclidean distance, 68,202 212-213 binding, 720,734-740,749 EUDOC Field-based descriptors, 201 transition-state analogs, 720, assessment, 303 Field effects, 140 748-754 ligand handling, 293 Field mapping, 107 Enzyme-mediated asymmetric European Bioinformatics Insti- Fields, 404 synthesis, 804-807 tute (EBI), 335 Filtercascade, 267 Enzymes sequence databases, 387 Filters, for searching, 315-316, as drug targets, 5 Everolimus, 849 376,380,392,404 kinetics, 725-728 Evolutionary algorithms, 299 Finasteride, 717,768 -770 pathways and inhibitor de- with QSAR, 53-54,61 Fingerprint Generation Pack, sign, 495 Exact match search, 378, 388 and structural genomics, 352 379-381,403 Fingerprints, 376,378,399,404 Ephedra, 885 Exchange repulsion energy, molecular similarity methods, Ephedrine, 884-886 172-173 188 (-)-Epibatidine,819 -820,821 Exemestane, 770,771 FIRM, 67 Epothilone A,864 Exhaustive mapping, 398 Fitness functions, 87-88 toxicological profile prediction, Expert Protein Analysis System, FK506 838-839 335 binding to FKBP, 552-555 Epothilone B, 864-865 Expressed sequence tags, 338 NMR spectroscopic binding Epothilone D, 865 expression level significance, studies, 539 Epoxides 342-344 FK506 binding protein inhibi- filtering from virtual screens, profiling, 341-342 tors, 552-555 246 Expression analysislprofiling, de novo design, 113 Equivalence class, 403 334 flexible docking studies, 265 Erythro-9-(2-hydroxy-3-nonyl) genome-wide, 344345 hydrogen bonding in, 288 (EHNA) for target discovery, 340-345 target of NMR screening stud- high-affinity adenosine deami- Extended stereochemistry, 365, ies, 565-566,571 nase ligand, 604 404 weak inhibitor screening, 319 Erythromycin, 870,871 External registry number, 379, X-ray crystallographic studies; Erythromycin macrolides, 404 487 874-876 Extrathermodynamic relation- Flat database storage, 362-363, Erythro- prefix, 784 ship, 26 404 Erythrose E,Z system, 365,399 Flat file storage, 360-362,404 enantiomers, 784 Flecainide E, constant (Taft), 23-24 Factorial designs, 65-66 enantiomers, 786 E-selectin Factor Xa inhibitors, 103, 738 FlexE, 301 NMR screening binding stud- 3D pharmacophores, 199 FlexibaseFLOG, 263 ies, 572 non-peptide peptidomimetics, Flexible ligands E-State index, 26,54 662.665 in docking methods, 293-294, Esters site-based pharmacophores, 322 pharmacophore points, 249 235-236 and geometric/combinatorial Estradiol, 706,771 target of structure-based drug search, 295 Estrogen receptor la design, 442 in virtual screening, 263-264 X-ray crystallographic studies, Fact tables, 390,401,404 Flexmatch index, 376 487 Failed Reactions database, 385 Flexmatch search, 404 Estrogen receptors Families, 93 FlexS, 316 mass-spectrometric binding Family competition evolutionary novel lead identification, 320, assay screening, 604 algorithm, 299 321 Ethacrynic acid FASTA, 347 PlexX antisickling agent, 421 Fast ion bombardment, 586,587 assessment, 303,304 Ethidium bromide Fastsearch index, 376377,399, consensus scoring, 266,320 thermodynamics of binding to 404 empirical scoring, 264,310 DNA, 183 FBSS, 202 explicit water molecules, 302 Index

hydrogen bonding, 319 4-Point pharmacophores, 408 GABA aminotransferase incremental construction, molecular similarity methods, (GABA-T) inhibitors, 718, 295-296 189,196-198,205 766-767 molecular modeling, 115 privileged, 231 X-ray crystallographic studies, novel lead identification, 320 virtual screening, 210 488 performance in structure pre- FPL-67047 p-D-Galactoside diction, 314 structure-based design, 453 saturation transfer difference protein and receptor model- Fractional factorial designs, 66 in binding to agglutin I, 569 ing, 267 Fragment analogs, 707-710 Galantamine (galanthamine), receptor representation in, Fragment-based ligand docking, 848,849,892-893 291 294 nonclassical resolution, 802, sampling/scoring methods FRED 803 used, 261 ligand handling, 293 GALOPED, 218 seeding experiments, 319 sampling/scoringmethods Gambler FlexXc extension, 318 used, 261 consensus scoring, 266 Flickering cluster model, of hy- Free energy of association, 286 flexible ligands, 263 drophobic interactions, 15 calculating, 180-181 seeding experiments, 319 Flo, 256 drug-receptor complexes, 5, Gas chromatography, 592 Flobufen, 41-42,42 170-171 for enantiomer separation, FLOG enzyme-inhibitor complexes, 787 explicit water molecules, 303 722 Gas chromatography-mass spec- ligand handling, 293 Free energy perturbation, 307, trometry (GC-MS), 585-586 and molecular size, 312313 308 GASP (Genetic Algorithm Simi- seeding experiments, 318 Free-Wilson approach, in QSAR, larity Program), 256 Flunet 4,29-30 in molecular modeling, 147 structure-based design, 451 Frontal affinity chromatogra- Gas phase association, 177, 178 Fluorescence spectroscopy, 592 phy-mass spectrometry, 601 G-CSF 3 4-Fluorobenzenesulfonamide 5-FSA X-ray crystallographic studies, binding to carbonic anhy- structure-based design, 424 488 drase, 538 FTDOCK, 115 Gelatinase 5'-p-Fluorosulfonylbenzoyl Ftrees-FS algorithm, 221 NMR binding studies, 555 adenosine (5'-FSBA), 763- Fujita-Ban equation, 4 Gel permeation chromatogra- 764 Fujita-Nishioka analysis, 13 phy-mass spectrometry, 599 5-Fluorouracil, 717, 718 GenBank, 335 Functional genomics, 338-340 Flurbiprofen, 763 growth of, 339 Functional group filters Fluvastatin, 744,879-880 X-ray crystallography applica- FOCUS-2D method, 68-69 in druglikeness screening, tion, 481 Fold compatibility methods, 353 246-247 GeneChips, 344 Fold patterns Functional mimetics (peptidomi- Gene expression, 351. See also limited number of, 353 metics), 636 Expressed sequence tags; Follicle stimulating hormone Fungal natural products, 848, Expression analysislprofil- X-ray crystallographic studies, 893 ing 488 Fungal squalene epoxidase in- Gene family approaches, 188, Force fields hibitors, 717 244 drug-target binding forces, Fungal sterol l4a-demethylase subset selection, 190-191 170-183 inhibitors, 717 Gene family databases, 347-349 molecular modeling, 79-81 Fuzzy bipolar pharmacophore Gene nomenclature, 337 parameter derivation, 102-103 autocorrelograms, 197 Gene Ontology project, 337 Force-field scoring, 264, Fuzzy clustering technique Generic structures, 367, 368, 306-308 with molecular similarityldi- 404-405 Formestane, 770, 771 versity methods, 205 Geneseq database, 346 Formula table, 376 Fuzzy distance, 57-58 Genetic algorithms FOUNDATION, 112-113 Fuzzy searches, 376 and combinatorial library de- Fourier transform ion cyclotron sign, 217,218 resonance (FTICR) mass G-4120,663 with docking methods, 292, spectrometry, 585,601-603 GABA, See y -Aminobutyric acid 298-299 Index

Genetic algorithms (Continued) Glutathione peroxidase empirical scoring, 309 with FOCUS-2D method, X-ray crystallographic studies, explicit water molecules, 303 68 - 69 488 hydrogen bonding, 107 inverse folding and threading, Glycinamide ribonucleotide and molecular modeling, 138 124-125 formyltransferase inhibi- Gridding and Partitioning (Gap) Larnarckian, 299 tors, 742-743 approach, 199,200 in molecular modeling, 87-89, target of structure-based drug GRIDIGOLPE analysis, 304305 117 design, 429-432 Grid tyranny, 91, 144 with QSAR, 53,61 Glycophorin A GRIND, 60 in virtual screening, 263 potential smoothing study of Groove-binding ligands, 5 GeneTox, 829 TM helix dimer, 86 Ground-state analog enzyme Genie Control Language, 378 Glycoprotein IIb/IIIa (GpIIb/ inhibitors, 720, 740-741 Genitoxants, 840 IIIa) inhibitors Growth hormone receptor Genome annotation, 481,494 non-peptide peptidomimetics, X-ray crystallographic studies, Genome-wide expression analy- 662-665 488 sis, 344345 template mimetics, 129, 643, Growth hormone secretagogues, Genomics, See Functional 645 671-672,675 genomics; Phylogenomics; Glycopyrrolate GS 4071 Structural genomics stereoisomers, 784-785 structure-based design, 452 GEOCORE, 124 Gmelin database, 386 Guanidine Geometric atom-pair descrip- GOLD pharmacophore points, 249 tors, 210 assessment, 303, 304 Gusperimus, 849 Geometric/combinatorialsearch empirical scoring, 309 strategies, 292,295 flexible ligands, 263 Hall databases, 387 Geometric hashing, 262 genetic algorithm, 299 Haloperidol Geometric isomer analogs, protein flexibility, 300 HIV protease inhibitor, 111, 704-707 sampling/scoring methods 112 Ghost membranes used, 261 Halopyrimidines EPR signal changes by ROH, GOLEM, 67 filtering from virtual screens, 27 GOLPE, 54,60 246 Ghrelin, 671, 674 GPCR libraries Hammett constants, 11,50 GHRP-6,671,674 3D pharmacophore finger- Hammett equation, 12, 13, 26, Gibbs-Helmholtz equation, 286 prints for, 205 50 Gigabyte, 405 GPCR-likeness, 251,252 Hamming distance, 202 GLIDE GPCRs (G-protein-coupled re- Harnmond postulate, 748 sampling/scoring methods ceptors), 668 Hanes-Woolf plot, 727, 729, 731 used, 261 focused screening libraries Hansch approach, to QSAR, Global stereochemistry, 398 targeting, 209,250 26-27,30 Glucocorticoid receptor homology modeling, 123, 150 Hansch-Fujita-Ban analysis, 31 X-ray crystallographic studies, molecular modeling, 122 Hansch parabolic equation, 3 488 peptidomimetics, 644, 677 Hansch-type parameters, 54 Glucose, 784 7-transmembrane, 229-234 HARPick program, 218,221 Glutamate dehydrogenase, 764 GRAB-peptidomimetic (Group- Hash code, 376,380,405 Glutamate NDMA agonists, 150 Replacement Assisted Bind- and combinatorial library de- Glutamate NDMA antagonists, ing), 636,658-659,677 sign, 223 150 GRAMM (Global Range Molecu- molecular fragment based, 54 Glutamate receptor 1 lar Matching), 115 Hemicholinium X-ray crystallographic studies, Granulocyte-macrophage CSF interatomic distance analogs, 488 X-ray crystallographic studies, 710-711 Glutamic acid 488 Hemoglobin chemical modification re- Graphical representation, 371 molecular modeling of crystal agents, 755 Graph isomorphism problem, structure, 105, 107 nonclassical bioisostere ana- 380,405 target of structure-based drug log, 694 GREEN design, 419-425 rigid analogs, 699 force-field scoring, 264 Hepatocyte growth factor activa- Glutamine-PRPP amidotrans- GRID, 58,315 tor inhibitor 1 ferase inhibitors, 717 3D pharmacophores, 198 mariptase inhibitor, 269,271 Index

Heroin, 849-850 HlV protease inhibitors, 717 Hydrofinasteride, 768,770 HE-State index, 26 binding-site molecular models, Hydrogen bonds, 285286,365 Heterochiral molecules, 782 130 acidic protons and .sr -systems, Heteronuclear multiple bond comparative molecular field 3 13 correlation spectroscopy analysis, 153 and empirical scoring, natural products, 518 consensus scoring study, 266 309-310 Heteronuclear single quantum 3D CoMFA, 59 enzyme inhibitors, 722, 724 correlation spectroscopy, de novo design, 113 hydrophobic interactions con- 512 force field-based scoring study, trasted, 319 Hexestrol, 707 307 molecular modeling, 81, Hierarchical clustering, 220, homology modeling, 123 107-108 401,405 knowledge-based scoring and QSAR, 6 with molecular similarityldi- study, 311 and structure-based design, 103-104, 409 versity methods, 205 molecular modeling, 105,108,109,111,117,120, Hydrolases High density oligonucleotide ar- 122 target of structure-based drug rays, 344 NMR binding studies, 533, design, 449-454 High performance liquid chro- 559-562 Hydrolysis matography (HPLC), non-peptide peptidomimetics, enzyme-mediated asymmetric, 586-589 659- 660 805-806 for combinatorial library novel lead identification by Hydrophobic bond, 15 screening, 592-596,598, virtual screening, 320 Hydrophobic effect, 178,182 599,607 seeding experiments, 318-319 Hydrophobic interactions, 50, fast, 596 target of structure-based drug 286,287-288 for hydrophobicity determina- design, 433-442 discovery of importance of, 3 tion, 16-17,23 transition state analogs, and empirical scoring, 310 for separation of chiral mole- 647-649 enzyme inhibitors, 724 cules, 783,788-792 and water, 302 hydrogen bonding contrasted, High-throughput chemistry, HIV reverse transcriptase inhib- 319 358,405 itors, 717 molecular modeling, 85, chemical libraries for, 367 X-ray crystallographic studies, 108-110 and natural product screen- 488-489 and QSAR, 6,7,1519,23,52 ing, 848 H+,K+-ATPaseinhibitors, 718 Hydrophobicity, 16-17 High Throughput Crystallogra- HKL suite, 478 determination by chromatog- Hoechst 33258 raphy, 17-18,23 phy Consortium, 418 binding to DNA, 544,547-552 (S)-3-Hydroxy-y-butyrolactone, High-throughput screening, 283 Homochiral molecules, 782 808,810 mass spectrometry applica- HOMO (Highest Occupied Mo- Hydroxychloroquine, 891 591,592-596 tions, lecular Orbital) energy, ll, 6R-Hydroxy-1,6-dihydropurine and molecular modeling, 155 14,54 riboside, 752 molecular similarityldiversity Homology, 348 Hydroxyethylurea, 153 methods, 191 and X-ray crystallography, 494 R-(-)-11-Hydroxy-10-methyla- raw data points obtained by Homology modeling, 261-262 porphine, 705 companies, 50 and docking methods, 305306 Hydroxymethylglutaryl-CoA with virtual screening, 316 molecular modeling, 123 (HMG-CoA) reductase in- X-ray crystallography applica- Homo Sapiens hibitors, 718,719, 744 -746 tion, 472 genome sequencing, 344 (f)-3-(3-Hydroxypheny1)-N-n- HIN file format, 369 HQSAR, 4 propylpiperidine (3-PPP), HINT descriptors, 56 HTML (HyperText Markup 704-705 Hint!-LogP, 389 Language), 371,405 D,L-3,5-Hydroxyvalerate,745 HipHop, 60,256 HUGO Gene Nomenclature HYPER, 727 Histamine antagonists Committee, 337 HypoGen, 256 molecular modeling, 143 Human Genome Database Hypothetical descriptor pharma- Histidine protein classes, 262 cophore, 63 chemical modification re- Human genome sequencing, 344 agents, 755 Human serum albumin, See Se- Iceberg model, of hydrophobic Hit list, 380,405, 411 rum albumin interactions, 15 Index

ICM targets: i.e., Dihydrofolate Interleukin 5 affinity grids, 293 reductase inhibitors X-ray crystallographic studies, homology modeling, 305 finding weak by virtual 491 ligand handling, 294 screening, 319 Interleukin 6 Monte Carlo minimization, not all are drugs, 408 X-ray crystallographic studies, 298 structure of free, and struc- 491 novel lead identification, 320 ture-based design, 409 Interleukin 8 ICGovalues, 731-732 In-house databases, 387-388 X-ray crystallographic studies, QSAR, 8 Inosine monophosphate dehy- 491 ID3,67 drogenase Interleukin 10 iDEA, 390 consensus scoring study, 266 X-ray crystallographic studies, IDEALIZE, 255 seeding experiments, 318-319 490 target of structure-based drug Identification. See also Lead Interleukin 12 design, 446-447 identification X-ray crystallographic studies, Inosine monophosphate dehy- 490 combinatorial library com- drogenase 2 pounds, mass spectrometry X-ray crystallographic studies, Interleukin 13 application, 596497 489 X-ray crystallographic studies, mass spectrometry applica- In silico screening, 191,244. See 490 tion, 594-596 also Virtual screening Interleukin-lp- converting en- Idoxuridine, 717 Insulin-like growth factor 1 zyme (ICE) Ifosfamide, 783 X-ray crystallographic studies, transition state analog inhibi- Imines 489 tors, 655 filtering from virtual screens, Insulin-like growth factor 2 Interleukin 1 receptor 246 X-ray crystallographic studies, X-ray crystallographic studies, Iminobiotin 489 490 binding to avidin, 181, 182 Insulin-like growth factor 1 re- Intermolecular forces, 6 Imipenem, 872-873,874 ceptor Interpro, 349 Imipramine X-ray crystallographic studies, InterProScan, 349 analogs, 692-693 489 Intracellular adhesion molecule Immobilized enzyme inhibitors, Integrin alphaM 1 (ICAM-1) 720 X-ray crystallographic studies, target of NMR screening stud- Immunophilins 489 ies using SAR-by-NMR, " chemical-shift mapping of Interatomic distance variant an- 566-567 binding to, 545 alogs, 710-712 Inventory data, 405 FK506 binding to FKBP, Intercellular adhesion molecule Inverse folding, 123-125 552-555 1 Inverse QSAR, 4 Importance sampling, 98 X-ray crystallographic studies, Inverted keys, 405 Incremental construction 489 Ionic bonds, 6, 170,365 in docking, 292,295-296 Interferon a 1 Ion-induced dipole interactions, in virtual screening, 262, X-ray crystallographic studies, 173 317-318 490 Ipconazole, 41 Indexes, 376-377,405 Interferon y Irinotecan, 849,861 Indinavir, 648,659 X-ray crystallographic studies, Irreversible inhibitors, 755 structure-based design, 490 ISISBase, 377,387 438-439,440,441 Interleukin 1 ISIS databases, 373,376-377, Indomethacin, 453 X-ray crystallographic studies, 387 Inductor variables, 25-26 490 descriptors, 192 Influenza virus neuraminidase Interleukin 2 exact match searching, 380 inhibitors, 717 X-ray crystallographic studies, similarity searching, 382-383 InfoChem ChemReactIChem- 490 substructure searching, 382 Synth database, 386 Interleukin 3 ISIS/Direct, 387 InfoChem SpresiReact database, X-ray crystallographic studies, ISIS/Draw, 387 386 490 Isomer search, 388,405-406 Infrared spectroscopy, 592 Interleukin 4 Isoprenaline, 885 Inhibitors. See also Enzyme in- X-ray crystallographic studies, Isotope editing and filtering, in hibitors; specific inhibition 490-491 NMR, 545,546 Index

Iterative cyclic approaches L-365,260,856 LH-RH antagonist, 634 and combinatorial library de- L-370,518, 660 LH-RH peptidomimetic analog, sign, 217 L-685,434 640 Ivermectin, 849,891,892 structure-based design, 439 LibEngine, 221 L-732,747 LiBrain, 220 Japanese Patent and Trademark structure-based design, 440, Libraries, 367, 400. See also Documents database, 386 441 Combinatorial libraries Jarvis-Patrick algorithm, 205,401 L-735,525, 797 focused screening libraries for and combinatorial library de- L-746,072,211 lead identification, 250-252 sign, 220,222 L1210 for NMR screening, 574576 Java, 396,406,407 growth inhibition, 37,40-41 QSAR for rational design of, JG-365,121,122 inhibition of DHFR, 32,34 68-69 Joins, 390,406 L. major DHFR, QSAR inhibi- Lidorestat Journal content searching, 383 tion studies, 33 structure-based design, Laboratory information manage- 448-449 Kaempferol, 865 ment systems, 377 Kanomycin, 870,871 p-Lactamase inhibitors, 718, Ligand-based design Karplus relationship, 525 868-874 NMR screening for, 564-577 Kelatorphan, 650,651 X-ray crystallographic studies, NMR spectroscopy for, 510, Kennard-Stone method, 65,66 483 517-532 Ketoconazole, 717 p-Lactams, 868-874 Ligand-based virtual screening, 8-Ketodeoxycoformycin, 751 Lamarckian genetic algorithm, 188 Ketol-en01 tautomerization 299 Ligand design, 110-118 NMR spectroscopy, 527-528 Lamivudine, 812-813,816 LigandFit Ketolides, 876 LASSO0 algorithm, 217 sampling/scoring methods Ketones Latent inactivators, 756 used, 261 pharmacophore points, 249 Latent semantic structure in- Ligand flexibility, See Flexible Key-based similarity searching, dexing, 255 ligands 382-383 Laudexium, 857,858 Ligands Key field, 406 Lead generation, 426 macromolecule-ligand interac- Keys, 363 Lead identification, 244 tions, NMR spectroscopy, encryption, 403 focused screening libraries for, 510,517,535-562 molecular similarity methods, 250-252 non-peptidic ligands for pep- 188 virtual screening for novel, tide receptors, 667-674 Khellin, 883, 884 320-321 visually assisted design, 110 Kinases Lead molecule fragment analogs, focused screening libraries 707-710 Ligand strain energy, 308 targeting, 250 Leaf nodes, 377 LIGSITE, 291 King's Clover, drugs derived Leave-one-out cross validation, Linear free energy relationship, from, 882 57,64 12,14 Kitz-Wilson plots, 757 Leave-some-out cross validation, Linear interaction energy K-means clustering, 401,406 64 method, 120 K-medoids clustering, 406 Legion, 387 Linear notation, 368-369,406 K-Nearest Neighbors, 53,62-63 Lennard-Jones potential, 285 Linear QSAR models, 26-28 KNI-272, 562 Lentinan, 849 descriptor pharmacophores, Knowledge-based scoring, Leucine aminopeptidase inhibi- 61 - 62 264-265,307,310-312 tors, 737-738 Linear regression analysis Knowledge-bases, 352,379 Leukocyte function-associated in QSAR, 8-11,50,53,67 Knowledge Discovery in Data- antigen 1 (LFA-1) Line-shape, in NMR, 512 bases (KDD), 394,406 target of NMR screening stud- and ligand dynamics, 528-531 Kohonen's Self-organizing Map ies using SAR-by-NMR, Lineweaver-Burk plot, 727, 729, method, 65,66 566-567 731 KOWWIN, 389 Leukotreine A4 hydrolase Link nodes, 381,397 Kubinyi bilinear model, 3,31 X-ray crystallographic studies, LINUS (Local Independent Nu- 491 cleating Units of Structure), Leveling effect, 722 124 Levorphanol, 708 Linux, 396,406,411 Index

Lipinski's "rule of 5" chromatographic determina- MACROMODEL, 94 and combinatorial library de- tion, 17-18,23 Macromolecular structure deter- sign, 214-215,216 estimation systems, 388,389 mination, 334 in druglikeness screening, 245 for molecular similarityldiver- NMR spectroscopy applica- for molecular similarityldiver- sity methods, 193,208 tions, 533535 sity methods, 193,208 and polarity index, 26 Macromolecule-ligand interac- and NMR screening, 575 Log Perm, 25 tions, See Protein-ligand Lipocortin I Log TA98,25-26 interactions X-ray crystallographic studies, Lomerizine, 41,42 Macrophage CSF 1 491 Lometrexol X-ray crystallographic studies, structure-based design, Lipophilic interactions, 286 491 429-430 Liquid chromatography MACROSEARCH, 94 London forces, See van der Magnetization transfer NMR, for enantiomer separation, Wads forces 787 568-570 Lopinavir, 648,659 Ma huang, 884-885 Liquid chromatography-mass asymmetric synthesis, 807, Mandelate racemase inhibitors, spectrometry (LC-MS), 809 762,763 586-591 Lorentz-Lorenz equation, 24 affinity screening, 598-599 Lovastatin, 878-879 Manhattan distance, 68 fast, 596 Low Mode Search, 292,301 Marcaine future developments, 607-608 LUDI, 259,295-296,315 classical resolution, 795 gel permeation chromatogra- combinatorial docking, 318 Marijuana, 853 phy screening, 599 empirical scoring, 310 Marine source drugs pulsed ultrafiltration screen- in molecular modeling, 112, antiasthma, 886 ing, 603-606 113 anticancer, 867-868 for purification of combinato- for novel lead identification, Markup languages, 371-372,405 rial libraries, 592-594 321 Markush feature, 381 structure/purity confirmation LUMO (Lowest Unoccupied Mo- Markush structures, 367,368, of combinatorial libraries, lecular Orbital) energy, ll, 373,406 594596 14,26, 54 MARPAT, 385 Liquid chromatography-NMR- Luteinzing hormone P Masoprocal, 849 MS, 608 X-ray crystallographic studies, Mass spectrometry, 583-592 Liquids 491 affinity capillary electrophore* force field models for simple, LwrS sis-mass spectrometry, 176 X-ray crystallographic struc- 599-600 Liquid secondary ion mass spec- ture elucidation, 494-495 affinity chromatography-mass LW-50020,849 trometry (LSIMS),586,587 spectrometry, 598-599 LY-303366,877 Lisinopril, 650, 881 bioaffinity screening using LY-315920 asymmetric synthesis, 807, electrospray FTICR MS, 809 structure-based design, 454 601 - 603 Literature content searching, Lycopene encoding and identification of 383 positive ion APCI mass spec- LitLink, 387 trum, 588 combinatorial compounds Local stereochemistry, 398 tandem mass spectrum, 591 and natural product ex- Lock-and-key hypothesis, 251, Lymphomas, 718 tracts, 596-597 252 Lysine frontal affinity chromatogra- deformable models, 5 chemical modification re- phy-mass spectrometry, 601 Locus maps, 140 agents, 755 future directions, 607-608 Log 1/C, 25,27-29 gel permeation chromatogra- Log CR, 25 MACCSSD, 259,363 phy-mass spectrometry, 599 Logic, in query features, 406 in molecular modeling, 111 LC-MS purification of combi- Logic and Heuristics Applied to MACCS (Molecular Access Sys- natorial libraries, 592-594 Synthetic Analysis tem), 254,361362 MS-based screening, 597-598 (LHASA), 379 Machine learning techniques pulsed ultrafiltration-mass Log MW,24 in molecular modeling, 151 spectrometry, 603-606 Log P in QSAR, 62 solid phase mass spectromet- chloroform-octanol, 17 Macrocyclic mimetics, 635-636 ric screening, 606-607 Index

structurelpurity confirmation Melittin 2-Methyl-1,4-benzenediol of combinatorial com- molecular modeling, 124 allergenicity prediction, 833 pounds, 594-596 Members, of Rgroups, 368,406 a-Methyldopa, 785 types of mass spectrometers, Membrane-bound drug targets, 5,lO-Methylene-tetrahydrofo- 585 351 late, 426, 427 Material Safety Data Sheets da- Membrane-bound proteins Methyl group roulette, 700 tabase, 386 molecular modeling, 154 Methylphenidate (Ritalin) Material Safety Data Sheet NMR structural determina- classical resolution, 793-794 searching, 384 tion, 535 nonclassical resolution, 801 Matriptase Membrane-bound receptors, 5 Metocurine, 856,857 virtual screening of inhibitors, Mepartrican, 849 Metoprolol 269-271,272 Meperidine, 708,851 renal clearance, 38 Matrix-assisted laser desorption rigid analog, 696 Metropolis algorithm, 94,98 ionization (MALDI), 586, 6-Mercaptopurine, 717 D,L-Mevalonate, 745 596,606-607 Mercury search program, 387 Mevastatin, 744-745 Matrix metalloprotease inhibi- Merged Markush Service, 386 MHC I receptor tors, 227,555457 Merimepodip homology modeling, 123 chemical-shift mapping of structure-based design, 447 molecular modeling, 117 binding to, 545 MERLIN, 39,386 Michaelis-Menten constants, target of NMR screening stud- Messenger RNA, See mRNA 725-728 ies using SAR-by-NMR, 566 Metabolism. See also Absorp- use in QSAR, 7,8 target of structure-based drug tion, distribution, metabo- Michaelis-Menten kinetics, design, 443-445 lism, and excretion (ADME) 725-728 transition state analog inhibi- enantiomers, 786-787 Microarray chips, 334,344-345 tors, 651-652 Metabolism databases, 385,386 Microbial secondary metabolites, virtual screening, 315 Metabolism screening, 591 848 Maximum Auto-Cross Correla- pulsed ultrafiltration applica- Micropatent, 386 tion (MACC),202 tion, 605 Microsoft Access, 373 Maxmin approach, 208 Metabolite database, 386 Middle tier, 392, 406-407 May apple, drugs derived from, Metadata, 375,376,406 Miglitol, 849 865 Meta-layer searching, 395 Milbemycins, 891,892 Maybridge catalog, 385 Metallopeptidase inhibitors L-Mimosine MCDOCK transition state analogs, analogs, 690 Monte Carlo simulated an- 649-652 MIMUMBA, 255 nealing, 297 Metamitron, 42 Mini-fingerprints, 255 MD Docking (MDD) algorithm, Metazocine, 708 Minimum topological difference 298 Metconazole, 41,42 (MTD) method, 4,147 MDL Information Systems, Inc. Methadone, 708 Mining minima algorithm, 292, databases, 386-387 Methamphetamine 299-300 Mechanism-based enzyme inhib- ring substitution analogs, 704 Mitogen-activated protein ki- itors, 759-760,764-771 R-Methanandamide, 852,853 nase Mefloquine, 889-890 Methanol target of structure-based drug artemisinin potentiates, force field models for, 176 design, 456-459 887-888 Methicillin, 869, 870, 871 Mivacurium, 857,859 Meglumine, 796-797 Methionine:adenosyl trans- Mixtures, 367-368 Melagatran ferase, 148 Mizoribine, 849 structure-based design, 442, Methionine hydrochloride MK-329,855 444 nonclassical resolution, 803 MK-383,213 a-Melanotropin Methods in Organic Synthesis MK-499,814-815,818 conformationally restricted database, 385 MK-0677,671,674 peptidomimetics, 637 Methotrexate, 717, 718, 749 MK-678,657 Melatonin interaction with dihydrofolate ML-236B, 879 analogs, 693 reductase, 120 MLPHARE, 478 antagonists, 211-212 structure-based design, 425 MM-25 Melilotus officinalis(ribbed me- N-Methyl-acetemide structure-based design, 423, Mot), 882 force field models for, 176 424 Index

common patterns, 142-150 Molecular structure descriptors structure-based design, 423, conformational analysis, 87, in QSAR, 26 424 93-94 Molecular targets, See Drug tar- MM2 force field, 80, 307 and electrostatic interactions, gets MM3 force field, 80, 118 81-85 Molecular weight MM-PBSA method, 315 and force fields, 79-81 for molecular similarityldiver- Modeling, See Molecular model- known receptors, 103-127 sity methods, 193,208 ing ligand design, 110-118 and QSAR, 24-25 Model mining, 3 molecular comparisons, MOLGEO, 255 Model receptor sites, 149-150 138-142 Molinspiration, 390 Molar refraction, 24, 54 and molecular mechanics, MOLPAT, 110-111 MOLCONN-Z, 55,192,389 79-100 Monasus ruber, 879 Molecular Biolom Database Col- pharmacophore versus binding Monoamine oxidase inhibitors, lection, 345 site models, 127-135 718 Molecular comparisons, 138-142 potential surfaces, 85-89 Monobactams, 873 Molecular connectivity, 192,407 estimation systems, 388 protein structure prediction, Monocolin K, 879 in QSAR, 26,55,56,61 122-127 Monomer Toolkit, 377378 Molecular docking methods, See and QSAR, 5 Monte Carlo simulated anneal- Docking methods and quantum mechanics, ing Molecular dynamic simulations. 100-103 and combinatorial library de- See also Monte Carlo simu- similarity searching, 135-138 sign, 218 lations site characterization, 105-110 with docking methods, 292, barrier crossing, 98 and statistical mechanics, 297 with docking methods, 292, 94 -95 with virtual screening, 263 298 in structure-based design, 419, Monte Carlo simulations. See and force field-based scoring, 420 also Molecular dynamic sim- 308 systematic search, 89-94, 116 ulations hydrogen bonds, 107 unknown receptors, 127-153 barrier crossing, 98 in molecular modeling, 85, 93, and virtual screening, 244 and combinatorial library de- 95-100,116-117,142 Molecular multiple moments, 54 sign, 217 and non-Boltzmann sampling, Molecular property visualiza- de novo design, 113 100 tion, 137-138 with docking methods, 292, protein flexibility, 301-302 Molecular recognition, 283 297-298 statistical mechanical, 94,95 and hydrophobic interactions, in molecular modeling, 85, 86, of temperature, pressure, and 15 93,96-99,116-117,142 volume, 96 physical basis of, 284-289 and non-Boltzmann sampling, thermodynamic cycle integra- Molecular replacement, 477 100 tion, 99 Molecular sequence alignment, statistical mechanical, 94,95 in virtual screening, 263 353 thermodynamic cycle integra- water's role in docking, Molecular sequence analysis tion, 99 302303 bioinformatics for, 335-336 in virtual screening, 263 Molecular eigenvalues, 54 Molecular shape analysis, 53 Moore's Law, 393 Molecular electrostatic potential, Molecular shape descriptors, 54 Morgan algorithm, 378,407 102 Molecular similarityldiversity Morphiceptin, 144,145 Molecular extensions, 130-131 methods, 54, 188-190 Morphinans, 850 Molecular field descriptors, 54, analysis and selection meth- Morphine, 634 55-57 ods, 203-209 ecological function, 848 Molecular Graphics and Model- combinatorial library design, fragment analogs, 707-708 ing Society, 360 190,214-228 Morphine alkaloids, 849-851 Molecular holograms, 54 descriptors for, 191-203 Mosflm/CCP4,478 Molecular mechanics, 79-100 example applications, 228-237 Most descriptive compound force fields, 174-177 future directions, 237 (MDC) method, 207-208 Molecular modeling, 77-79, and molecular modeling, mRNA 153-154,358 135-138 and expression profiling, affinity calculation, 118-122 virtual screening by, 188,190, 340-341 and bioinformatics, 351 209-214 MSDRLICSIS, 361 Index

MS-MS, See Tandem mass spec- enzyme-mediated asymmetric X-ray crystallographic studies trometry (MS-MS) synthesis, 805 [int B virus], 491 Mulliken population analysis, Narwedine, 802,803 Neuroleptics 101-102 National Cancer Institute data- molecular modeling, 150 MULTICASE SAR method base, 222,254,385486,387 Neuromuscular drugs toxicity prediction application, National Center for Biotechnol- natural products as leads, 828 - 843 ogy Information (NCBI), 856-858 Multidimensional databases, 335 Neuropeptide Y 390,407 sequence databases, 387 X-ray crystallographic studies, Multidimensional NMR spec- National Toxicology Program, 492 troscopy, 512-514 246,829 Neuropeptide Y inhibitors, 671, Multidimensional scaling, 201 Natural product mimetics, 636 673,674 Neutral endopeptidase (NEP), Multidimensional scoring, 291 Natural products 650-651 Multilevel chemical compatibil- antiasthma drug leads, Nitric oxide synthase, 736 ity, 249 883-886 Nitric oxide synthase inhibitor, Multiple-copy simultaneous antibiotics drug leads, 738-739 search methods (MCSS), 868-878 Nivalin, 892 298 anticancer drug leads, NK receptor antagonists, Multiple isomorphous replace- 858 - 868 669-670,672 ment (MIR) phasing, 477 antiparasitic drug leads, NMR, See Nuclear Magnetic Multiple regression analysis 886-891 Resonance (NMR) spectros- in QSAR, 8-11,50,52,53 cardiovascular drug leads, COPY Multisubstrate analog enzyme 878-883 NMR timescale, 537 inhibitors, 720, 741-748 CNS drug leads, 849-856 NN-703,671,675 Multi-tier architecture, 392, 407 drugs derived from, NOE, See Nuclear Overhauser Multiwavelength anomalous dif- 1990-2000,849 effects (NOE), in NMR fraction (MAD) phasing, extract encoding and identifi- Nolatrexed, 428 474,477-478 cation, 596-597 Non-Boltzmann sampling, 100 Munich Information Center for leads for new drugs, 847-894 Nonclassical bioisosteres, Protein Sequences (MIPS), neuromuscular blocking drug 690-694 335 leads, 856-858 Nonclassical resolution, of chiral Muscarinic receptors NMR structure elucidation, molecules, 799-804 distance range matrices, 136 517-518 Noncompetitive inhibitors, stereoisomer analogs, 705-706 Natural products databases, 387, 730-731 Mutation 597 Noncovalent bonds, 6,170 in genetic algorithms, 87,88 Nearest neighbors methods, 53, energy components for inter- MVIIA (Ziconotide) 62-63,67 molecular drug-target bind- NMR spectroscopy, 518-523, Neighborhood behavior, 211 ing, 171-174 526,534 Nelfinavir, 648 Noncovalently binding enzyme MVT-101,103-104,105,117 asymmetric synthesis, inhibitors, 720-754 Mycophenolate mofetil, 849 817-818 Nonisosteric bioanalogs, Mycophenolic acid structure-based design, 440, 689-694 structure-based design, 442 Nonlinear QSAR models, 28-29 446-447 Neomycin, 870,871 descriptor pharmacophores, Myoglobin, 419 Netropsin 62- 63 binding perturbations, 544 Nonlinear regression, 67 Nabilone, 853 Neu5Ac2en Non-overlapping mapping, 398 Nadolol structure-based design, 451 Non-peptide peptidomimetics, renal clearance, 38 Neural networks, See Artificial 636,657-674 Naftifine, 717 neural networks Nonpolar interactions, See van Na+,K+-ATPaseinhibitors, 718 Neuraminidase inhibitors, 717 der Wads forces Nalorphine, 850 flexible docking studies, 265 Nonstructural chemical data, Naloxone, 850 PMF function application, 314 373 NAPFMLERT, 597 Screenscore application, 319 Norapomorphine Naproxen target of structure-based drug alkyl chain homologation ana- classical resolution, 794-795 design, 450-452 logs, 701 Index

Norfloxacin, 41,42 for macromolecular structure OSPPREYS (Oriented-substitu- Norstatine, 652 determination, 533 ent Pharmacophore PRop- Norvir and NMR screening, 571-573 ErtY Space), 199,224 structure-based design, 438, NOE docking, 545-546 Overlapping mapping, 398 440 transferred NOE technique, OWFEG (one window free en- Nostructure, 410 532 ergy grid) method, 308,315 NOT logical operator, 406 Nucleic acid receptors, 5 Oxidation NPS 1407,812,815 Nucleic acids. See also DNA, enzyme-mediated asymmetric, Nuclear hormone receptors RNA 806 focused screening libraries biochemical force fields, Oxidoreductases targeting, 250 175-176 target of structure-based drug NMR structural determina- design, 445-449 Nuclear Magnetic Resonance tion, 535 Oxprenolol (NMR) imaging, 510 Nucleotide intercalation, 183 renal clearance, 38 Nuclear Magnetic Resonance Oxytetracyclin, 870 (NMR) screening methods, 0 (graphics program), 478 510,562-577 Object-oriented language, 407 P. carinii DHFR, QSAR inhibi- capacity issues, 190 Object relational database, 407 tion studies, 32-33 Nuclear Magnetic Resonance Ocreotide, 657 Pacific yew, paclitaxel from, (NMR) spectroscopy, 351, Octanol/water partitioning sys- 861-862 507-514,592. See also SAR- tem, 16-17 Paclitaxel, 843,848,861-863 by-NMR approach OLAP (OnLine Analytical Pro- Pairwise interactions, 79-80 applications, 516417 cessing), 390,408 PALLAS System, 389 chemical shift mapping, Oleandomycin, 870,871 Paluther, 887 543-545 OLTP (OnLine Transaction Pro- Pamaquine, 888 - 889 instrumentation, 514-516 cessing), 390,408 Pancreatic polypeptide with LC-MS, 608 Omapatrilat, 651 molecular modeling of avian, ligand-based design, 510, OMEGA, 255 124 517532 Ondanetron Papain macromolecule-ligand interac- nonclassical resolution, 802 QSAR studies, 5 tions, 510, 517, 535-562 OpenBabel, 372 transition state analog inhibi- metabolic, 510 Open Molecule Foundation, 360 tors, 654 and molecular modeling, 78 Open reading frames Papaver somniferum (opium . multidimensional, 512-514 housing in DNA databases, POPPY), 848,849 for pharmacophore modeling, 338 Parallel chemistry, 283 531-532 Opium poppy, 848,849 Parallel library, 214 receptor-based design, 510, Optimization approaches Parallel processing, 408 532-562 for combinatorial library de- Parathion, 774 in structure-based drug de- sign, 217-220 Parathyroid hormone sign, 419,516-517 OptiSim method, 207 X-ray crystallographic studies, and structure-based library and combinatorial library de- 492 design, 225 sign, 220 Parent structure, 368,404 structure determination of Oracle, 373 Pareto optimality, 220 bioactive peptides, 517-518 Organic structure databases, Partial charge, 366,373 structure elucidation of natu- 385 Partition coefficients, 16-17, 54 ral products, 517-518 Organoarsenical agents, 717 Partition function, 94-95 and virtual screening, 244 Orientation map (OW),131, Partitioning algorithms, 67 Nuclear Magnetic Resonance 144,146 PASS, 291,390 (NMR)titrations, 545 Oriented-substituent pharma- Patent Citations Index, 386 Nuclear Overhauser effect cophores, 224 Patent databases, 386 (NOE) pumping, 573 Orlistat, 848,849 Patent searching, 383-384 Nuclear Overhauser effects OR logical operator, 406 Pathways, 495-496 (NOE), in NMR, 511,512 use in molecular similarity1 X-ray crystallographic analy- for conformational analysis, diversity methods, 194 sis, 495-496 525 Ornithine decarboxylase inhibi- Pattern recognition, 408 and distance range matrix, tors, 717, 766, 768, 769 and cluster analysis, 401 136 Oseltamivir, 452, 717 with QSAR, 53 PC cluster computing, 283-284 Pfam, 349 target of structure-based drug PCModels, 386 Pharmacophore keys, 376, design, 453-454 PD-119229 408-409 X-ray crystallographic studies, structure-based design, Pharmacophore mapping, 255 492 460-461 Pharmacophore point filters, Phosphonoacetate, 740 PDB file format, 369 196,249-250 N-Phosphonoacetyl-L-aspartate PDGF beta Pharmacophores, 368 (PALA), 743-744 X-ray crystallographic studies, with BCUT descriptors, Phosphonoformate, 740 492 223-224 2-(Phosphonomethoxy)ethylgua- Peak intensities, in NMR, 512 binding site models con- nidines Peldesine trasted, 127-135 chain branching analogs, 702 structure-based design, 460 defined, 252-253,408 (R)-9-[2-(Phosphonome- Pemetrexed descriptor, for QSAR,60 -63 thoxy)propylladenine (R- structure-based design, 3D searching, 366-367 PMPA), 818-819 429-430 in molecular modeling, 110 Phosphoryl transferases Penicillins, 717,868-870 for molecular similarityldiver- preventing bacterial degrada- sity methods, 194-201, target of structure-based drug tion, 718 204-206 design, 456-4561 Penicillipepsin inhibitors NMR-based modeling, Phylogenomics, 347-349 molecular modeling, 116 531-532 Physicochemical descriptors, 54 Penicillium brevicompactum, NMR spectroscopy-based mod- estimation systems, 389 879 eling, 531532 for molecular similarityldiver- Penicillium chrysogenum, 869 oriented-substituent, 224 sity methods, 193 Penicillium citrinium, 879 site-based, 235-237 for virtual screening, 255 Pentostatin, 717, 750-751,849 virtual screening, 252-260 Physicochemical properties, 373, PeptiCLEC-TR, 804 PharmPrint method, 223 409 Peptide backbone mimetics, 636, Phase problem Physostigmine, 774 644 - 645 in X-ray crystallography, Picornaviruses Peptide bond isosteres, 644-646 476-478 target of structure-based drug Peptides, 634 Phencyclidine design, 454-456 biochemical force fields, rigid analogs, 696-697 Picovir 175-176 P-Phenethylamines, 697-698 structure-based design, NMR structural determina- Phenols 455-456 DNA synthesis inhibition by, tion of bioactive, 517-518 Pigeon liver DHFR, QSAR inhi- non-Boltzmann sampling of 40 bition studies, 31-32 helical transitions, 100 growth inhibition by, 38, Peptidomimetics, 128-129, 40-41 Pipecolic acid, 805 633-634 Phenylacetic acids Pirlindole classification, 634-636 ionization of substituted, chromatographic separation, conformationally restricted 12-14 788-789,790 peptides, 636- 643 Phenylethanolamine N-methyl- Pit viper, drugs derived from, future directions, 674-677 transferase (PNMT) inhibi- 881 molecular modeling, 154 tors, 733-734,740 Pivoting data, 409 non-peptide, 636,657-674 (R,S)-a-Phenylglycidate,762 Plant natural products, 848,893 peptide bond isosteres, (S)-a-Phenylglycidate, 762 Plant secondary metabolites, 644-646 N'-(R-Pheny1)sulfanilamides 848 protease inhibitors, 646-655 antibacterial activity, 10 Pleconaril speeding up research, 655-657 Phosphatidylcholine monolayers structure-based design, template mimetics, 643-644 penetration by ROH, 27 455-456 Peramivir Phosphocholine PLOGP, 389 structure-based design, 452 docking to antibody McPC603, PLP function, 266,309 Personal chemical databases, 298 consensus scoring, 320 387-388 Phosphodiesterases hydrophobic interactions, 319 Petabyte, 408 alignment of catalytic domains performance in structure pre- Pethidine, 851 in gene family, 349 diction, 314

PETRG 390 Phos~holi~ase* - A2 seeding experiments, 319 Petrosia contignata, 886 homology modeling, 123 PLUMS, 225 p38 MAP kinase Prinomastat target of structure-based drug consensus scoring study, 266 structure-based design, 444, design, 432-445 seeding experiments, 318319 446 transition state analogs, PMF function, 265,311,312 PRINTS, 335,349 646-655 performance in structure pre- Privileged structures Protein classes, 262 diction, 314 in molecular similarity/diver- Protein Data Bank, 110,353 seeding experiments, 319 sity methods, 209 sequence database, 387 PMML (Predictive Model template mimetics, 644 X-ray crystallography applica- Markup Language), 405 in virtual screening, 251-252 tion, 478-479 PNU-107859 PROBE, 126 Protein Database NMR binding studies, 555 PROCHECK program, 478 and virtual screening, 261-262 PNU-140690,659,812,813 ProDock Protein families PNU-142372 affinity grids, 293 targeting in libraries for vir- NMR binding studies, tual screening, 251 Monte Carlo minimization, 555-556 Protein interactions, 334 298 POCKET, 259 Protein-ligand docking pro- 349 Podophyllin ProDom, grams, 292 drugs derived from, 865-867 Proflavin Protein-ligand docking tech- Podophyllotoxin, 849,865-866 thermodynamics of binding to niques, 262-264 Podophyllum emodi, 865 DNA, 183 Protein-ligand interactions, Podophyllum peltatum (May ap- Progesterone receptor 284-289,322 ple), 865 antibody FAB fragment, 128 NMR spectroscopy, 510,517, Poisson-Boltzmann equation, X-ray crystallographic studies, 535-562 83,84 492 QSAR studies, 5 Polarity index, 26 PROGOL, 67 scoring, 264-267 Polarizability, 85 Project Library, 387 scoring in virtual screening, Polarizability index, 11 Prolactin receptor 264-266 Polarization energy, 173 X-ray crystallographic studies, Protein-protein interactions, 634 Polar surface area 492 characterizing,637 in druglikeness screening, 245 PRO-LEADS, 299 Proteins. See also Macromolecu- Policosanol, 849 assessment, 303,304 lar structure determination Pomona College Medchem, 385 flexible ligands, 263 binding and chirality, 786-787 Potassium channel shaker PRO-LIGAND flexibility and docking, X-ray crystallographic studies, genetic algorithm with, 89 300-302,322 492 Pronethalol, 881 phylogenetic profiling, Potential smoothing, 86 Propargylglycine, 719-720 347-348 Potential surfaces, 85-89 Property-based design, 234-235 Protein structures PPAR y Propranolol, 881-882 prediction, 122-127 X-ray crystallographic studies, enantiomers, 786 in structure-based virtual 492 enzyme-mediated asymmetric screening, 261-262 Pralnacasan synthesis, 805-806 X-ray crystallographic analy- structure-based design, 443, renal clearance, 38 sis, 496 446 N10-Propynyl-5,8-dideazafolate, Proteome, 352 Pravastatin, 879,880 426,427 Proteomics. 409 Preliminary screening, 11 1-112 Proresid, 866-867 Pseudoirreversible enzyme in- Pressure PRO-SELECT hibitors, 771-774 molecular dynamic simula- combinatorial docking, 318 Pseudomonas acidophila, 873 tion, 96 PROSITE, 348349 Pseudopeptides, 635-636 Primaquine, 889 Prostacyclin, 762-763 isosteres replacing peptide Principal components analysis Prostaglandin synthase inhibi- backbone groups, 646 with molecular similarityldi- tors, 718,762 -763,764 Pseudoracemate, 799-800,801 versity methods, 192,201 Protaxols, 863 Pseudo-receptor models, 261 in QSAR, 15 Protease inhibitors. See also PSI-BLAST, 335,347 Principal components regres- HIV protease inhibitors X-ray crystallography applica- sion, 53 affmity labels, 762 tion, 481 Prindolol QSAR studies, 5 Pulsed ultrafdtration-mass spec- renal clearance, 38 structural genomics, 353 trometry, 603-606 Index

Purine biosynthesis inhibitors, descriptor pharmacophore Racemates, 782 752 concept, 60-63 types of, 799-801 Purine nucleoside phosphorylase and docking methods, Racemization, 783-784 target of structure-based drug 304-305 Radiation damage design, 459-461 Free-Wilson approach, 4, in electron cryomicroscopy, Purine ribonucleoside, 751-752 29-30 612-613,614-615,616 Purity verification guiding principals for safe, 66 Raffinate, 791 as bottleneck in drug discov- and library design, 68-69 Ramachandran plot, 92 ery, 592 linear models, 26-28, 51, and conformational mimicry, LC-MS-based purification, 61-62 141 592-594 model validation, 63-66 Ramipril, 746 mass spectrometry applica- and molecular similarity/di- Ramiprilat, 746-747 Random searching tion, 594-596 versity methods, 194 in virtual screening, 263 Pyridoxal phosphate-dependent multiple descriptors of molec- Rapamycin, 848 enzymes ular structure, 54-58 binding to FKBP, 552,554 mechanism-based inhibitors, nonlinear models, 28-29, 51, Rapid, reversible enzyme inhibi- 765-768 62-63 tors, 720,728-734 Pyrimidine biosynthesis inhibi- parameters used, 11-26 Rapid sequence screening, 334 2 tors, 752 problems with Q , 64-65 Rare gas interactions, 174 Pyrrolinones receptor theory development, Ras-farnesyltransferase inhibi- peptide-like side chains, 635, 4-7 tors 642 standard table, 51 non-peptide peptidomimetics, Pyruvate dehydrogenase inhibi- in structure-based design, 419 665-667,668,669 tors, 717 substituent constants for, template mimetics, 643,645 Pyruvate kinase, 764 19-23 Rats taxonomy of approaches, ataxia induction by ROH, 29 Qinghaosu (artemisinin), 886 52-54 liver DHFR, QSAR inhibition Q-jumping MD, 298 tools and techniques of, 7-11 studies, 34 QSAR, See Quantitative struc- training and test set selection, REACCS, 398 ture-activity relationships 65-66 reaction searching using, 383 QSAR and Modeling Society, 360 variable selection. 60-63 Reactant-biased, product-based QSDock, 295 as virtual screening tool, (RBPB) algorithm, 215,216, QSiAR, 53,60 66-69 219 QSPR, See Quantitative struc- Quantitative structure-property Reacting centers, 366,383, 398, ture-property relationships relationships, 53 409 Quadratic shape descriptors, 295 and molecular similarityldi- Reaction Browser~Web,387 Quadrupole time-of-flight hybrid versity methods, 194 Reaction databases, 386 (QqTOF) mass spectrome- Quantum chemical indices, 11, Reaction field theory, 83 try, 585,607 14-15,54 Reaction indexing, 383 QUANTA, 258 Quantum mechanics, 100-103 Reaction Package, 386 Quantitative strudure-activity Quercetin, 865 Reactions, See Chemical reac- relationships, 1-4,49-52, Query features, 381 tions 358. See also Comparative logical operators, 406 Reaction scheme, 409 quantitative structure-activ- Query structures, 368 Reagent Selector, 387,391-392 ity relationships; 3D quanti- mapping, 380 RECAP (Retrosynthetic Combi- tative structure-activity re- Quinacrine, 889,890-891 natorial Analysis Proce- lationships Quinine, 888-891 dure), 249 applications with interactions Quinolines, 889-890 Receptor-based design at cellular level, 37-38 Quinupristin, 876-877 NMR spectroscopy for, 510, applications with interactions Quisqualic acid, 694 532-562 in vivo, 3839 Qxp pharmacophore generation, applications with isolated re- Monte Carlo minimization, 259 ceptor interactions, 30-37 298 Receptor-based 3D QSAR, 304 2D, 52,53 Receptor-ligand complexes, 78 data mining, 66-67 Rabbits Receptor-ligand mimetics, 636 defined, 409 narcosis induction by ROH, 27 Receptor mapping, 148-149 Index

Receptor-relevant subspace, 204, RGD peptide sequence mimics, ROSDAL notation, 368,410 222 129,643,645,662-665 Rosuvastatin, 848,880-881 Receptor theory, 4-7 Rgroups, 368,373,397,405, Rosy periwinkle, vinca alkaloids Reciprocal nearest neighbor, 220 409-410 from, 858 Recursive partitioning, 247-248 and combinatorial library de- Rotatable bonds Red clover extract sign, 221 in druglikeness screening, 245 LC-MS mass spectrum, 589, Rhinoviruses in molecular modeling, 90-91 590 comparative molecular field Royal Society of Chemistry Reduction analysis, 153 Chemical Information enzyme-mediated asymmetric, molecular modeling of antivi- Group, 360 806 ral binding to HRV-14, 120, RPR109353,211 Refining, search queries, 409 122 R,S descriptors, for chiral mole- target of structure-based drug REFMAC, 478 cules, 365, 783 design, 454-456 Registration, of chemical infor- RS3 Discovery System, 377,385 Rhodopeptin mation, 377-379 template mimetics, 644,645 RSR-13,422,423 Registry number, 378-379,409 Ribbed melilot, drugs derived RSR-56,422,423 Relational databases, 363, 373, from, 882 RTECS, 246 409 Rifamycin, 870,872 RUBICON, 386 Relative diversitylsimilarity, 209 Rigid analogs, 694-699 virtual screening application, Relaxation parameters, in NMR, Rigid body rotations, in molecu- 254 511,512 lar modeling, 90-91 "Rule of 5," See Lipinski's "rule changes on binding, 536-537 Rigid docking, 262-263,293 of 5" and ligand dynamics, 528-531 Rigid geometry approximation, and NMR screening, 571-573 in molecular modeling, 89 S-37435,675 in receptor-based design, 534 Ring-position isomer analogs, Saccharomyces cerevisiae Relenza 699-704 genome sequencing, 344 structure-based design, 451 Rings Saccharopolyspora erythraea, Relibase, 315 in druglikeness screening, 245 874 Reminyl, 892 molecular comparisons, 139 Salbutamol, 885,886 Renin inhibitors, 432 in molecular modeling, 91 Salmeterol, 885,886 molecular modeling, 123, 153 Ring-size change analogs, S-Salmeterol transition state analogs, 647 699-704 enzyme-mediated reduction, REOS filtering tool, 225 Ritalin 806,808 RESEARCH classical resolution, 793-794 Salmonella Monte Carlo simulated an- nonclassical resolution, 801 mutagenicity prediction, 829, nealing, 297 Ritonavir, 648,659 831-832,840,842-843 Resiniferatoxin, 854 asymmetric synthesis, Salt bridges, 285 Restrained electrostatic poten- 807-808,809 and virtual screening, 272 tial, 102 structure-based design, 438, Salts definitions, 376 Result set, 409,411 440 Salts search, 388 Retigotine, 783 Rivastigmine, 774 Sampatrilat, 651 Retinoic acid structure-based design, Saquinavir, 648,659, 717 docking and homology model- 449-450 structure-based design, ing, 305 RNA 435-437,440 stereoisomer analogs, 707 molecular modeling, 154 SAR-by-NMR approach, 508, X-ray crystallographic studies, NMR structural determina- 516 492-493 tion, 535 in NMR screening, 564468, Retinoid X receptor RNA polymerase inhibitors, 717 576 X-ray crystallographic studies, Ro-31-8959, 121 Sarin, 774 493 Ro-32-7315, 652, 653 Saturated rings Retrosynthetic analysis, 409 Ro-46-2005,673, 676 analogs based on substitution Retrothiorphan, 650, 651 ROCS, 256,259 of aromatic for saturated Reverse nuclear Overhauser ef- shape-based superposition, ring; or the converse, fects pumping, 573 260 699-704 Reversible enzyme inhibitors, Roll-up, 410 Saturation diversity approach, 720 Root structure, 368,404,410 223 Index

Saturation transfer difference Serevent, 806 Simulated annealing. See also NMR, 568-570 Serial analysis of gene expres- Monte Carlo simulated an- SB203580 sion (SAGE), 344 nealing structure-based design, 457 Serine and combinatorial library de- SB209670,211,675 chemical modification re- sign, 217 SB214857,213 agents, 755 with FOCUS-2D method, 68 SB242253 Serine peptidase inhibitors hydrogen bonds, 107 structure-based design, 458 transition state analogs, in molecular similarityldiver- Scaled particle theory, 84 652-655 sity methods, 205 SCH 47307,667 Serine protease inhibitors with QSAR, 53,61 in virtual screening, 263 SCH 57939,808,810 affinity labels, 762 Simulated moving bed chroma- SCH 66701,667 common structural motifs, Schrodinger equation, 79,363 494 tography for enantiomer separation, Scientific and Technical Infor- QSAR studies, 5 mation Network, 597 787,789-793,821 Serotonin SciFinder, 385 Simvastatin, 719, 744,879,880 conformationally restricted SCOP, 353 Single nucleotide polymorphism X-ray crystallography applica- analog, 696 (SNP) maps, 338-340 tion, 494 ring position analogs, 703-704 Single-wavelength anomalous ScoreDock Serotransferrin p diffraction phasing (SAD), assessment, 303 X-ray crystallographic studies, 477-478 Scoring functions, 261,264-266, 493 Sirolimus, 848,849 306-312,322 Serum albumin Site-based pharmacophores, assessment, 312-315 binding of enantiomers, 786 235-237 basic concepts, 289-290 mass-spectrometric binding Size-exclusion chromatography, and molecular modeling, assay screening, 604 599 115-116 target of NMR screening stud- Sizofilan, 849 overview of, 307 ies, 567-568,573 SKI? 107260,663 penalty terms, 313 SFCHECK program, 478 SLIDE Screening. See also Combinato- Sgroups, 373,397,405,410 anchor and grow algorithm, rial chemistry; High- Shake and Bake, 477,478 296 combinatorial docking, 317 throughput screening; Vir- SHAPES explicit water molecules, 302 tual screening NMR screening libraries, 575 geometric/combinatorial mass spectrometry-based, and SAR-by-NMR, 568 search, 295 597-598 SHARP, 478 solid phase mass spectromet- ligand handling, 293 SHELX, 478 ric, 606-607 protein flexibility, 301 Sialic acid, 450-451 Screenscore, 319 receptor representation in, Sculpt, 387 Sialidase 291 SEAL, 316,321 genetic algorithm study of SLN (Sybyl Line Notation), 369, Search queries, 368 docking, 88-89 410 p-Secretase inhibitors Sickle-cell anemia, 419-425 Slow-binding enzyme inhibitors, transition state analogs, 649 Side chains 720,734-740,749 Selector, 387 of known drugs, and druglike- Slow-tight-binding enzyme in- SELECT program, 218-219,221 ness screening, 248-249 hibitors, 720, 734-740 SELECT statement, 404,406 peptide-like, 635, 642 SMART, 349 Self-organizing Map method, Signature functional group filters, 246 65,66 molecular similarity methods, SMILES notation, 254,410 Semirigid analogs, 694-699 188 and canonical renumbering, Sequence assembly, 342 Similarity searching, 379, 378 Sequence comparison, 334 382483,410. See also Mo- described, 368-369,371 bioinformatics for, 346-347, lecular similarityldiversity use with comparative QSAR, 352-353 methods 39 Sequence databases, 387 in molecular modeling, SmoG, 311 Sequences, 363364 135-138 SN-6999,544 Sequential docking, 317 and QSAR, 67-68 Snowdrops, drugs derived from, Sequential simplex strategy, 11 SQL for, 395 892 Index

SNX-111,851-852 Stereoplex, 387 nonlinear, 62 SOCRATES, 361 Stereoselective synthesis, See pharmacophore searching for Sodium cromoglycate, 883-884 Asymmetric synthesis generating, 255,272-273 Soergel distance, 68 Steric parameters and toxicity prediction, Solid Phase Synthesis database, in QSAR, 23-25,52 828 - 843 385 STERIMOL parameters, 24, 50 Structure-based drug design, Solution molecular dynamics, Steroid 5a-reductase inhibitors, 358,417-419,467-469 528 717,768-770 antifolate targets, 425-432 Solvation effects QSAR studies, 37-38 and combinatorial chemistry, and docking scoring functions, Steroids 227 307,308,310 affinity for binding proteins, combinatorial library design, drug-receptor complexes, 147 225-228 177-179 biosynthesis inhibition, 770 and docking studies, 282, molecular modeling, 83-85 STN Express, 385 321-322 SOLVE, 478 STN International, 385 hemoglobin, 419-425 Somatostatin STO-3G basis set, 175 conformationally restricted Storage, of chemical informa- hydrolases, 449-454 peptidomimetics, 129,637, tion, 373-377 iterative cycles, 282,463 638 Streptavidin NMR spectroscopy for, 419, receptor agonists found free energies of binding, 286 516-517 through combinatorial genetic algorithm study of bi- oxidoreductases, 445-449 chemistry, 657 otin docking to, 89 phosphoryl transferases, template mimetics, 643-644, interaction with biotin, 456-461 645 181-183 picornaviruses, 454-456 Sorangium cellulosum, epothi- Streptogramins, 876-877 proteases, 432-445 lones from, 864 Streptomyces, 876,891 and virtual screening, 244 SPC model, 175 Streptomyces cattleya, 872 Structure-based inhibitor de- Specific structure, 368,403 Streptomyces clavuligerus, 869 sign, 418 Sphere coloring, 296 Streptomyces erythreus, 874 Structure-based virtual screen- Sphere-exclusion, 207 Streptomyces griseus, 869 ing, 260-267 Spindle poisons, 867 Streptomyces venezuelae, 870 Structure elucidation Spin-label NMR screening, Streptomycin, 869-870 NMR spectroscopy for, 573-574 Stromelysin 517-525 SPLICE, 89,113 flexible docking studies, 265 Structure table, 376 Spongothymidine, 867-868 NMR binding studies, Structure verification Spongouridine, 867-868 555-557 as bottleneck in drug discov- SPRESI, 254 target of NMR screening stud- ery, 592 SPRESI'95,385 ies using SAR-by-NMR, 566 mass spectrometry applica- SQL (Structured Query Lan- target of structure-based drug tion, 594-596 guage), 395,410 design, 443-444 Subgraph isomorphism, 67,405, SR-48968,670 Structural data mining, 410 410 SR-120107A, 670,673 Structural frameworks of known Subreum, 849 SRS (Sequence Retrieval Sys- drugs Substance P antagonists, tem), 335 and druglikeness screening, 669-671 Standardization 248-249 Substances, 368,410 bioinformatics, 337 Structural genomics, 283 Substituent constants, for Star schema, 390,391,410 and bioinformatics, 352354 QSAR, 19-23 Statins, 719,848 and X-ray crystallography, Substrate analog enzyme inhibi- multisubstrate analogs, 481,494-496 tors, 733 744-746 Structural homology, See Ho- Substructure searching, 255, Statistical mechanics, 94-95 mology 379,381-382,410-411 Stem cell factor Structural similarity, 255 and QSAR, 67 X-ray crystallographic studies, Structure-activity relationships. SQL for, 395 493 See also Quantitative struc- Substructure search keys, 375, Stereoisomer analogs, 704-707 ture-activity relationships 376,378,410 Stereoisomers, 365-366, and data mining, 66-67 molecular similarity/diversity 783-785 and molecular modeling, 134 methods, 189,221 Index

Subtilases T. gondii DHFR, QSAR inhibi- TB36 homology modeling, 123 tion studies, 33 structure-based design, Succinate dehydrogenase, 733 Tabular storage, 369-371 424-425 Succinic semialdehyde dehydro- Tabu search TBC 3214,674,676 genase inhibitors, 718 with docking methods, 292, Team Works, 377 Succinyldicholine 299 Teicoplanin, 849 conformationally restricted in virtual screening, 263 Telithromycin, 848,876 analogs, 699 Tachykinin receptors, 669 Temperature Sugars Tacrine, 58 molecular dynamic simula- chirality, 784 structure-based design, 449 tion, 96 Suicide substrate MMP inhibi- Tacrolimus, 848,849 Template mimetics (peptidomi- tors, 651-652 Tadpoles metics), 643- 644 Suicide substrates, 756 narcotic action of ROH, 28-29 Tendamistat Sulbactam, 718 NMR relaxation measure- Tagging approaches, 596-597 Sulfonamides ments, 528-529,535 TAK-029,213 pharmacophore points, 249 Teniposide, 867 Sulfones TAK-147 Teprotide, 746,881 pharmacophore points, 249 structure-based design, 450 Terabyte, 411 Sulfonyl halides Tandem mass spectrometry Terbinafine, 717 filtering from virtual screens, (MS-MS), 590-591 Testosterone, 36, 768, 771 246 of combinatorial libraries, 592 A,-Tetrahydrocannabinol Sulphonamides, 717 for structure determination of (THC), 852-853 Supercritical fluid chromatogra- bioactive peptides, 518 Tetrahydrofolate, 425 P~Y types of mass spectrometers, Tetrahymena pyriformis for enantiomer separation, 585 growth inhibition, 27,37-38 787 Tanimoto coefficient, 68,202, spiro-Tetraoxacycloalkanes Supercritical fluid chromatogra- 411 ring-size analogs, 702-703 phy-mass spectrometry cluster-based methods with, Tetrazoles, 135 (SFC-MS) 206 as surrogates for cis-amide for combinatorial library puri- and similarity searching, 382, bond, 141-142 fication, 594 410 Thalidomide, 783-784,785 Superstar, 315 for virtual screening, 210 Thebaine, 850,851 Superstructure search, 255,257, Tanimoto Dissimilarity, 220 Theilheimer/Chiras/Metalysi 411 Tanomastat database, 386 Supervised data mining, 66-67, structure-based design, Therapeutic area screening 411 444-445,446 molecular similarityldiversity Suxamethonium, 857 TargetBASE, 348 methods, 191 Sweet clover, drugs derived Target class approach, 188, Thermodynamic cycle integra- from, 882 228-234 tion, 99-100,120-121 Sweet wormwood, drugs derived Target discovery. See also Drug Thermolysin inhibitors from, 886 targets genetic algorithm study of ac- SWISS-PROT, 335,345-346 bioinformatics for, 335, tive site, 89 SYBYL, 130 338-345 molecular modeling, 11 7, 120, Sybyl Programming Language, TAR RNA inhibitors, 103 121,151-153 378,410 Tautomenzation novel lead identification, 321 Synercid, 848,849, 876 NMR spectroscopy, 526-528 transition-state analogs, SYNLIB, 361 Tautomers, 366 749-750 SYSDOC Tautomer search, 388,405-406 Thick clients, 400-401,411 ligand handling, 293 Taxol, 843,848,861-863 Thienamycin, 872,874 Systematic search HMBC spectroscopy, 518 Thin clients, 363,392,401,411 and Active Analog Approach, NMR spectroscopy, 525-526, Thiobiotin 144-145 531 binding to avidin, 181, 182 and conformational analysis, Taxol side-chain, 803-804 Thioesters 89-93 Taxus baccata (English yew), filtering from virtual screens, in docking methods, 292 861-862 246 in molecular modeling, 89-94, Taxus brevifolia (Pacific yew), p-ThioGARdideazafolate (P-TG- 116 861-862 DDF), 742-743 Index

Thiol proteases Thromboxane 4,762-763 Toxicity screening QSAR studies, 5 Thymidine kinase inhibitors, as bottleneck in drug discov- Thiomuscimol, 690 717 ery, 592 4-Thioquinone fluoromethide, role of water in docking, 303 and functional group filters, 770 X-ray crystallographic studies, 246-247 Thioridazine, 805,806 493 pulsed ultrafdtration applica- Thiorphan, 650,651 Thymidylate synthase inhibi- tion, 605 Thor database manager, 386 tors, 227, 717 Toxicophores, 829- 831 Thor system, 377 target of structure-based drug associated with allergic con- exact match searching, design, 425,426-429 tact dermatitis, 830 380381 Thymitaq, 428 C-Toxiferine 1,856,857 Threading, 123-125 Thyroid hormones TPCK, 760-761,762 3D descriptors NMR spectroscopy, 529-531 Tramadol, 782 molecular similaritytdiversity Thyroid receptor beta, 263 chromatographic separation, methods, 55-58,191-201 Thyroliberin validation, 211-213 peptidomimetics, 129 792 Three-dimensional electron Thyrotropin-releasing hormone, classical resolution, 795-796 cryomicroscopy, 615616 637 metabolism, 786-787 3D models, 363,366-367, Thyroxine Transesterification 397-398 NMR spectroscopy, 529-531 enzyme-mediated asymmetric, 3D pharmacophores Tight-binding enzyme inhibi- 805-806 filter cascade, 267 tors, 720, 734-740, 749 Transferred NOE technique, for molecular similarityldiver- Time-of-flight mass spectrome- 532 sity methods, 194-201 try, 585,607 and NMR screening, 572-573 for searching, 381-382 Timolol Transition-state analog enzyme similarity searching, 189,383 renal clearance, 38 inhibitors, 720, 748-754 for virtual screening, 210, TIP3P model, 175 Transition state analog inhibi- 255-259 Tipranavir, 812, 813 tors, 646 3D quantitative structure-activ- Tirilazad mesylate, 849 peptide bond isosteres, 644 ity relationships (3D- Titrations 7-Transmembrane G-protein- QSAR), 52,53,58-60 NMR application, 545 coupled receptors, 229-234 and molecular modeling, 115, TNF-a converting enzyme Transpeptidase inhibitors, 717 138 (TACE), 652 Transverse relaxation-optimized 3D query features, 368,381382, Tolamolol spectroscopy (TROSY), 515 398 renal clearance, 38 for macromolecular structure 3DSEARCH, 111,259 Tolrestat determination, 533,534 3D structure databases, 387 structure-based design, 448 Trees, 376377,411 3-Point pharmacophores, 376, Tomudex, 427 TrEMBL, 335,346 408 Toolkits, 386,411 Triazines molecular similarity methods, Toothpick plant, drugs derived QSAR studies of cellular 189,195196,198 from, 883 growth inhibition, 37-38 for virtual screening, 210 TOPAS, 192 QSAR studies of DHFR inhibi- Threo- prefix, 784 TOPKAT, 246 tion, 31-33 Threose Topographical data, 411 Trimethoprim, 717, 719 enantiomers, 784 Topographical mimetics (pep- interaction with dihydrofolate Thrombin inhibitors, 227 tidomimetics), 636 reductase, 151,183 combinatorial docking, 318 Topoisomerase I1 inhibitors, 717 structure-based design, 425 force field-based scoring study, Topological descriptors a,@-bis-Trimethylammonium 307 for druglikeness screening, polymethylene compounds, molecular modeling, 116 247-249 710 non-peptide peptidomimetics, estimation systems, 388-389 Trimetrexate 660-662,663,664 with QSAR, 54-55 interaction with dihydrofolate seeding experiments, 319 Topotecan, 848,849,861 reductase, NMR spectros- site-based pharmacophores, Torsional potential, 80 copy, 531,557-559 235-236 Toxicity databases, 246,386 Triple resonance spectra, 514 target of structure-based drug development, 828 -829 Tripos, Inc. databases, 387 design, 442-443 Toxicity prediction, 827-843 Tripos force field, 80 t-RNA guanine transglycosylase Uncompetitive inhibitors, Virtual libraries, 237, 283,315 inhibitors 729-730 handling large, 220-221 novel lead identification, 321 Unicode, 411 and QSAR, 61 Trojan horse inactivators, 756 UNITY, 259,377 Virtual rings, 91 Trypsin inhibitors descriptors, 192,201 Virtual screening, 244-245, molecular modeling, 120 in molecular modeling, 111 271-274,315-317,412. See QSAR studies, 5, 25 novel lead identification, 320 also Docking methods; Scor- site-based pharmacophores, UNITY 2D, 212 ing functions 235-236 UNITY 3D, 363,387 applications, 267-271 Trypsinogen inhibitors University of Manchester Bioin- basic concepts, 289-290 molecular modeling, 116 formatics Education and combinatorial docking, Tryptophan Research site (UMBER), 317-318 chemical modification re- 335 consensus scoring, 265-266, agents, 755 Unix, 396, 411 291,319-320 TSCA database, 386 Unsupervised data mining, docking as virtual screening Tubby gene 66-67,412 tool, 266-267 X-ray crystallographic func- Urea druglikeness screening, tion elucidation, 494 pharmacophore points, 249 245-250 Tube curare, 856 Ureido resonance, 182 filter cascade, 267 D-Tubocurarine USEPA Suite, 390 focused screening libraries for drugs derived from, 856,857 lead identification, 250-252 fragment analogs, 708-710 VALIDATE, 116,310 hydrogen bonding and hydro- p-Tubulin Vancomycin, 770 phobic interactions, 319 X-ray crystallographic studies, Vancomycin-peptide complex ligand-based, 188,209-214 483 binding affinity, 119 molecular similarityldiversity Tumor necrosis factor receptor 1 van der Waals forces, 174,285 methods for, 188, 190, X-ray crystallographic studies, and docking scoring, 308 209-214 493 enzyme inhibitors, 723-724 novel lead identification, 2D descriptors and molar refraction, 24 320-321 molecular similarityldiversity molecular modeling, 79-80, pharmacophore screening, methods, 191-194 81, 82, 89 252-260 with QSAR, 54-55 and QSAR, 6,7 QSAR as tool for, 66-69 validation, 211-213 van der Waals radius, 79,81, seeding experiments, 318-319 2D pharmacophore searching, 173 structure-based, 260-267 383 Vanillin weak inhibitors, 319 filter cascade, 267 antisickling agent, 419-420 Vista search program, 387 virtual screening, 255 Vanilloid receptors, 853-854 Vitamin D receptor 2D quantitative structure-activ- VanX inhibitors, 770-771, 772 X-ray crystallographic studies, ity relationships (2D- VARCHAR data type, 412 493 QSAR), 52,53 VARCHAR2 data type, 412 VK19911 2D query features, 397 Vector maps, 140-142 structure-based design, 458 2D structures, 364366,397 Verapamil Voglibose, 849 conversion of names to, 373 classical resolution, 798 VolSurf program, 202 2-Point pharmacophores, 376 Verapamilic acid, 798 Volume Tyrosine Vidarabine, 717 molecular dynamic simula- chemical modification re- Vigabatrin, 718,766, 767,782 tion, 96 agents, 755 Vinblastine, 858-859,860 Volume mapping, 139-140 Tyrosine kinase inhibitors Vinca alkaloids, 858-860 Voronoi QSAR technique, 53 molecular modeling, 130 Vincristine, 858-859,860 VRML (Virtual Reality Markup Vindesine, 859-860 Language), 405 U-85548 Vinorelbine, 849 VX-497 structure-based design, Viracept, 659 structure-based design, 447 436-437,438 structure-based design, 440, VX-745 Ugi reaction, 229,231, 232, 236 442 structure-based design, 458 UK QSAR and Cheminformatics Viral DNA polymerase inhibi- Group, 360 tors, 717 Warfarin, 882-883 Ukrain, 849 Virtual chemistry space, 67 enantiomers, 786 Warfarin (Continued) WIN-63843 and molecular modeling, 78 HIV protease inhibitor, 659, structure-based design, phase problem, 476-478 661 455-456 and QSAR, 5 nonclassical resolution, 801 Wiswesser line notation, and structural genomics, 481, WARP, 478 368-369 494-496 Water WIZARD, 255,260 in structure-based drug de- gas phase association thermo- World Drug Index (WDI), 379, sign, 418,419,420 dynamic functions, 178 386,387 and structure-based library importance of bound in struc- World Patents Index (WPI), 386 design, 225 ture-based design, 409 and virtual screening, 244 Xanthine-guanine phosphoribo- molecular modeling, 85 X-ray diffraction, 472-473, 614 syltransferase octanoVwater partitioning sys- X-ray crystallographic studies, X-ray lenses, 612 tem, 16-17 493 and protein-ligand interac- Xanthine oxidase inhibitors, 718 Yellow sweet clover, drugs de- tions, 288 XFIT graphics program, 478 rived from, 882 role in docking, 302-303, Ximelagatran Yew tree, paclitaxel from, 313-314 structure-based design, 442 861-862 solvating effect in enzyme in- XML (extensible Markup Lan- YM-022,856 hibitors, 722-723 guage), 371,405,412 Yukawa-Tsuno equation, 14 Wellcome Registry, 222 XMLQuery, 412 White-Bovill force field, 80 X-ray crystallography, 351, Z-100,849 WIN-35065-2 471-473,612 Zanamivir, 717 dopamine transporter inhibi- applications, 479-481 structure-based design, 451 tor, 268 crystallization for, 473-474, Ziconotide WIN-51711 480-481 NMR spectroscopy, 518-523, structure-based design, databases for, 478-479 526,534 454-455 data collection, 474-476 Zidovudine, 717 WIN-54954 drug targets with published Zingerone structure-based design, 455 structures, 482-493 allergenicity prediction, 835 "An essential addit to the libraries o . . . an outstanding work . . . highly information in drug studies and research. --Toozzmal of Medicinal Chenzi

This new edition of Dr. Alfred Burger's internationally celebrated classic helps researchers acquaint themselves with both traditional and state-of-the-art principles and practices governing new medicinal drug research and development. Completely updated and revised to reflect the many monumental changes that have occurred in the field, this latest edition brings together contributions by experts in a wide range of related fields to explore recent advances in the understanding of the structural biology of drug action, as well as cutting-edge technologies for drug discovery now in use around the world. This Sixth Edition of Burger's Medicinal Chemistry and Drug Discovery has been expanded to six volumes: Volume 1: Drug Discovery Volume 2: Drug Discovery and Drug Developme1 Volume 3: Cardiovascular Agents and Endocrines Volume 4: Autocoids, Diagnostics, and Drugs from New Biology Volume 5 : Chemotherapeutic Agents Volume 6: Nervous System Agents

UUNALD A. ABRAHAM, PHD, is Proiessor and Chairman of the Department of Medicinal Chemistry at the Virginia Commonwealth University School of Pharmacy. A world-renowned leader in medicinal chemistry and biotechnology, he is the author of more than 140 journal citations and twenty-five patents. He was selected by the AACP Board of Directors as the recipient of the 2002 Ar? ? P ' D2xxrqon Biotechnology Award.