Pharmaceutical (Medicinal) Chemistry Introduction
Pharmaceutical (medicinal) chemistry
Introduction
PharmDr. Pavol Ježko, PhD. Department of Pharmaceutical Chemistry Faculty of Pharmacy, Comenius University Odbojarov 10, 832 32 Bratislava, Slovakia Tel: + 421 250 117 395 e-mail: [email protected] ; [email protected] 1 1 Definition ofofpharmaceutical chemistry
• pharmaceutical chemistry – discovery – development – identification and interpretation of the mode of action of biologically active compounds at the molecular level
• pharmaceutical chemistry is an interdisciplinary science • pharmacology, biochemistry, molecular biology, imunology (life sciences) • organic, physical, theoretical chemistry, molecular spectroscopy, crystallography, (chemical sciences) • information technology
2 Drugs
• Organic (inorganic) compounds and biomolecules (proteins, antibodies, …) that activates or inhibits the function of a target with benefit to the patient
activity (target binding place stereoelectronic compatibility)
low toxicity (selectivity, antitargets: CYP, hERG, P-glycoprotein...)
bioavailablity (physico-chemical and pharmacological properties ensuring drug-likeness) Three main phases of drug action
• pharmaceutical phase (biopharmaceutical) release of drug from the drug form
• pharmacokinetic phase (wh at makes the body with the drug) ADME
• pharmacodynamic phase (what makes the drug with the organism) character and quality of drug interactions with interaction site of the biological system
4 Basic terms in pharmaceutical chemistry
• TARGET (biomacromolecule to interfere with) • BINDING POCKET – ACTIVE SITE (part of the target appropriate to bind a small ligand) • PHARMACOPHORE (a part of a molecule that is recognized at a receptor site and is responsible for that molecule's biological activity) • LIGAND organic molecule possessing target affinity, that has to be stereo- electronically compatible with binding pocket ACTIVE is a compound detected by usually HTS HIT is a active compound identified in a screen with confirmed structure and activity , that need to be developed into lead compound LEAD is a active compound with convenient properties : drug-likeness, solubility, synthetic feasibility, patentability DRUG CANDIDATE high activity, good selectivity, in vivo efficiency DRUG after success in clinical trials approved by FDA, EMEA • DRUG-LIKENESS complex properties – (ADME/Tox : Absorption/ Distribution/ Metabolism/ Excretion/ Toxicity) Drug development basic chronology
selection of disease (cardiovascular, autoimmune, infectious, hereditary, mental, cancer …)
molecular mechanism of the pathology (medicine, molecular biology)
selection of a key biomolecule to influence
new active structure/compound identification: in Silico design, HTS, of organic molecules possessing appropriate drug-like properties (biologists, computer chemists)
organic synthesis (chemists)
biological or biophysical assays (biologists)
optimization of activity and other molecular properties
IP protection + clinical trials + up-scale synthesis + approval Pharmaceutical chemistry includesincludes::
•• The process ofof discovery = identification and production of new active compounds natural resources synthesis biotechnology design - computer aided drug design (CADD)
• The optimization process synthetic modification of the lead sceleton (structures) to improve the effect , selectivity and suppress toxicity (S.A.R.)
• The development process optimization of synthetic processes for mass production of the drug modification of pharmacokinetic properties of the drug (suitable for clinical use) 7 From were to get active compounds?
Micro-organisms (bacteria, fungi) Marine chemistry (corals, bacteria, fish etc) Plant life (flowers, trees, bushes) A) The Natural World Animal life (frogs, snakes, scorpions) Biochemicals (neurotransmitters, hormones) Pure natural products, bioextracts (e.g. plant, or microbial) Ethnopharmacology (Chinese traditional medicine...)
LMW synthetic compounds B) The Synthetic World (traditional, combinatorial synthesis, historical corporate chemical collections, commercial sources)
C) The Virtual World Computer aided drug design (CADD) to call them „active compounds“ evaluation through biological screening is essential Pharmaceutical research and development (R & D)
• discovery of a new lead sceleton is a key step in any research program
• nowdays it is also the most problematic stage of development of a new drug
Discovery of new lead structures in 70s 20 th century - random selection (random observation, a happy discovery, screening a large number of compounds)
Nowdays: racional procedures • based on the knowledge structure of endogenous metabolites, enzymes, receptors and the nature of the biochemical defect that caused the disease
9 Structure – activity relationship
• primary task of the medical chemist is to identify leading sceleton and its subsequent modification in order to obtain a suitable candidate to drug that may be introduced into clinical practice
• leading structure may have some deficiencies, chemical and biological characteristics: a lack of specificity, low activity, metabolic, chemical instability, high toxicity, low bioavailability, poor solubility
• irrational approach: make all the easy and available variations of the leading sceleton
• rational process: methods and approaches that describe the relationship between drug structure and its activity - knowledge of the spatial (3D) structure of the receptors at atomic level resolution) - knowledge of the conformation of ligands and their interaction with target 10 macromolecules Strategies ofofmodification existing structuresructures
• by chemical modification will be prepared new compounds, which will have higher activity, lower toxicity, or better dosage form
11 Bioisosteric substitution
• is based on the knowledge that certain physical properties of chemically different compounds are strikingly similar
• bioisosters are considered a group of compounds which have the chemical and physical properties that produce similar biological effect
12 Classical bioisosters
• Are of similar size, shape and valence electron configuration
Classical isosters that can serve as bioisosters:
monovalent atoms and groups bivalent atoms and groups
A: –CH 3 –NH 2 –OH –F –Cl A: –CH 2– –NH– –O– –S– –Se–
B: –Cl –PH 2 –SH B: –COCH 2– –CONH – –COO – –COS – C: –Br –i-Pr D: –I –t-Bu ring equivalents trivalent tetravalent A: –CH=CH– –S– (benzene; tiophene) A: –CH= –N= A: >C< >Si< B: –CH= –N= (benzene; pyridine) B: –P= –As= B: =C= =N += =P +=
C: –O– –S– –CH 2– –NH– (tetrahydrofurane; tetrahydrotiophene; cyclopentane; pyrrolidine) 13 Nonclassical bioisosters
Nonclassical bioisosters of Carbonyl group R R CN R R O R CN R HC • Are of different number O SO S R SO2 N R R O R of atoms, do not meet R CN R R Nonclassical bioisosters of Carboxyl group the steric and electron COOH SO NHR SO H 2 3 N OH O H C rules of classical CONHCN CONHOH 3 N bioisosters, but evoke PO(OH)OEt PO(OH)NH2 ON O N N OH H similar biological activity Nonclassical bioisosters of Ester group N S RR RR R R COO R NOMe NO N R Nonclassical bioisosters of Amide group R R
R CONH R R CONMe R R CSNH RR CH2NH R CC R CH2S R Nonclassical bioisosters of Hydroxyl groupRR R NHSO R R CH OH R OH R NHCOR 2 2 R NHCONH2 R NHCN R CH(CN)2 Nonclassical bioisosters of Catechol group HO N O O
X N HO N HO HO H X = O, NR Nonclassical bioisosters of Halogen
Halogen CF 3 CN NCN 2 C(CN) 3 Nonclassical bioisosters of Urea-like 14 NHC(=S)NH 2 NHC(=NCN)NH 2 NHC(=CHNO 2)NH 2 15 Systematic screening
• systematic testing of new compounds without the known mechanism of action and pharmacological potential
• extensive screening - a comprehensive pharmacological assessment is subjected to a limited number of “advanced“ structures
• random screening - from large number of compounds (hundreds-thousands) is looking for one which is active in the indication 16 The use of biological information
• monitor the effects of random compounds for new discoveries about biological processes taking place in biology and medicine
– observation of people - folk medicine (Digitalis, opiates, quinine, atropine, cocaine)
– observations in animals - in vivo pharmacological tests on animals (Vinca rosea - vincristine, vinblastine) 17 Rational drug development
• rational design consist of the knowledge of the molecular level of the disease
18 GeneticsGenetics,, genomics and drugdevelopment • Over the last 15 to 25 years there has been progress in several scientific fields, particularly combinatorial chemistry, genomics, proteomics and bioinformatics, which are promise for the future in a streamlining of procedures discovering new drugs.
• The main idea of new methods of research and drug development is to identify the biological action, gene or protein that is disrupted in the disease process.
• Then, on the basis of this knowledge could be design a drug that specifically interact with the site of action 19 Computational pharmaceutical chemistry
20 Computational pharmaceutical chemistry
• Computational chemistry – is a discipline using mathematical methods for the calculation (computer-assisted) of molecular properties or for the simulation of molecular behaviour – most used methods • quantum mechanics • classical mechanics
• Computational pharmaceutical chemistry – Main object of study • drugs • biological systems associated with drugs (proteins, enzymes, receptors...) 21 Drug design and development
Drug-like molecule
• Necessary condition – biological activity = f (3D structure + physicochemical properties )
• Sufficient condition – high-affinity ligand must exhibit also good pharmacokinetic and toxicological properties • pharmacokinetic ADMET (Absorption, Distribution, Metabolism, Excretion and toxicity ) parameters • (poor biopharmaceutical properties and toxicity are one of the major reason for drug development failure)
22 Molecular modeling and medicinal chemistry
• Molecular modeling methods – Quantum chemistry – Molecular Mechanics – Molecular Dynamics and Monte Carlo
23 Electronic structure methods • semi-empirical methods (MNDO, AM1, PM3, ...) – programs: MOPAC, HyperChem, Gaussian, ...
• ab initio methods – Hartree-Fock methods – electronic correlation methods • Moller-Plesset Pertubation Theory (MP2, MP3, MP4, MP5)
• Density functional methods – B3LYP, B3P86, BLYP, ...
• Hybrid methods – ONIOM, QM/MM approaches – Programs: Gaussian, Jaguar,...
• Use of these methods: – Geometry and energy calculations • in gas phase • solvent effect 24 ComputerComputer--AssistedAssistedDrug Design
•• CADD ((ComputerComputer--AssistedAssisted Drug Design)) Design was developed by applying methods and theories of computational chemistry to study the properties of drugs
• can be applied to any active molecules, which interact with the receptor is known
25 Computer-assisted drug design (CADD)
• Computer-assisted drug design – involves all computer-assisted techniques used to discover, design and optimize biologically active compounds with a putative use as drugs
• CADD is the science and art of finding molecules of potential therapeutic value that satisfy a whole range of quantitative criteria such as high potency, high specificity, minimal toxic effect and good bioavailabity
• CADD relies on computers, information science, statistics, mathematics, physics, biology and medicine
• CADD implies the use of computer graphics to visualize and manipulate chemical structures, to synthesize “ in silico “ new molecules, to determine their conformation, and to assess the similarities aind dissimilarities between series of molecules
• CADD also involves the calculation of the interaction energy between drug molecules and hypothetical or experimentally determined macromoleculas structures 26 Computer assisted drug design
AIM: • to discover, enhance, study biologically active molecules that will bind to a selected target and if so how strongly before a compound is synthesized
• to estimate drug-like properties and use them for elimination of undesirable structures
• it still takes several iterations of design, synthesis, and testing before an optimal molecule is discovered Target selection
Do we Do we know 3D know 3D structure structure ? of homolog protein?
SBDD LBDD
What What compound compound ? ?
New lead Optimized New lead Optimized compound structure compound structure
Database Design Database Design searching de novo searching de novo
Molecular Fragment Active Pharmacophore QSAR docking docking analog model model model 28 Rational methods in drug design
• Structure-based drug design SBDD
• Ligand-based drug design LBDD
• Fragment-based drug design FBDD Structure Based Drug Design - SBDD
• relies on knowledge of the 3D structure of the biological target obtained through X-ray crystallography or NMR spectroscopy
• SBDD be divided roughly into two categories • “finding” ligands for a given receptor (database searching). A large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. It saves synthetic effort to obtain new active compounds.
• “building” ligands (receptor-based drug design). In this case, ligand molecules are built up within the constraints of the binding pocket by assembling small pieces (atoms, fragments) in a stepwise manner. The key advantage is that novel structures, not contained in any database, can be suggested . Ligand Based Drug Design LBDD (indirect DD)
• relies on knowledge of known molecules that bind to the
biological target (known: structure and bioactivity IC 50 )
• These molecules (ligands) may be used to derive a pharmacophore model which defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target.
• Virtual screening (based on pharmacophore models; high-throughput docking) including drug property filtering (Zinc database)
• Alternatively, a quantitative structure-activity relationship (QSAR ) in which a correlation between calculated properties of molecules and their experimentally determined biological activity may be derived. These may be used to predict the activity of new analogues . Pharmacophore
• spatial (3D) arrangement of functional groups of ligand molecules that react with the active site of the receptor
• actually defines "natural" dimensions of the ligand molecule
32 EGFR inhibitor gefinitib (IRRESA) (approved for refractory lung cancer, AstraZeneca)
EGFR (ErbB, HER1) tyrosine kinase receptor : abnormal or over-expressed in the breast, lung, brain, prostate, gastrointestinal tract, ovaries cancer . EGFR is a receptor for EGF proteins (1986 Nobel Prize). Upon activation by its growth factor, EGFR forms active homodimer possessing intracellular TK activity that initiate several signal transduction cascades leading to DNA synthesis and cell proliferation . Gefitinib inhibits EGFR by binding to the ATP-binding site . Thus receptor and therefore also malignant cells are inhibited . 4-anilinoquinazoline SAR optimized main metabolic products I, II both met. routes Lead I, good in vitro activity, in vivo blocked hampered by rapid metabolism Cl- similar in size and lipophilicity as Me- group caused by cytochrome P450 F- almost the same size as H- (no steric effect) enzymes both groups are resistant to oxidation, better in vivo activity, pharmacokinetic properties improved by morpholino group, because of basic nitrogen that enhanced water solubility What should compound fulfill to become a drug?
• Biol. active, chemically stable compound possessing appropriate: pharmacodynamic properties (activity, selectivity) pharmacokinetic properties (bioavailability: ADME/TOX) others (novelty, scale up synthesis...) • > 30% of all drug failures can be attributed to poor physiochemical
properties : Log P (Log D), pK a, and solubility all have impacts on drug absorption and diffusion in vivo
Chemical Space
Lead-like Drug-like Chem Space: 10 60 - 10 200 Drugs DB of 11 atoms C,N,O, F: 26 400 000 stable compounds (110.9 M if stereoisomers included) J.-L. Reimond J. Chem. Inf. Model. 47, 2007, 342. Bioavailability
• (in vitro) active compound, to perform as drug, has to reach its target in the human body (in vivo )
• Drug-likeness is qualitative concept to estimate bioavailability from the molecular structure before the substance is synthesized . The drug -like molecule has to have :
optimal MW and number of HBD , HBA (affecting solubility and absorption)
optimal water and fat solubility logP (octanol / water) (intestinal lining, aqueous blood, penetrate cellular membrane to rich inside the cell) The distribution coefficient (Log D) is the correct descriptor for ionisable systems. log D is pH dependent (e.g. at pH = 7.4 is the physiological pH of blood serum)
Lipinski's Rule of Five (Ro5) Lipinski Ro5 (all numbers are multiples of five, empiric rule) for prediction of bioavailability (not activity !) to quickly eliminate compounds that have poor physicochemical properties for oral bioavailabilty • an orally active drug has no more than one violation of the following criteria : MW ≤ 500 Lipophilicity (logP ≤ 5) octanol-water partition coefficient (better log D ≤ 5 respecting the ionic states present at physiological pH values) Sum of hydrogen bond donors ≤ 5 (NH,OH) Sum of hydrogen bond acceptors ≤ 10 (N,O)
C. A. Lipinski et al. Adv. Drug Del. Rev. 1997 , 23, 3. (Ro5) Greg M. Pearl et al., Mol. Pharmaceutics, 2007, 4, 556–560. (log D introduced) Additional drug-like parameters
MW ≤ 500 Lipophilicity (logP ≤ 5) octanol-water partition coefficient Sum of hydrogen bond donors ≤ 5 (NH,OH) Sum of hydrogen bond acceptors ≤ 10 (N,O)
PSA < 140 Å 2(Molecular Polar Surface Area – sum of surfaces of polar atoms (N,O...with H) that correlates with human intestinal and BBB absorption) for good BBB penetration ( PSA < 60 Å 2) Number of rotatable bonds < 10 (flexibility factor) (high NRB → many conformers)
Ertl, P. in Molecular Drug Properties, R. Mannhold (ed), Wiley-VCH , 2007 , 111 – 126 . Ro5 determined from 2D tructure http://www.molinspiration.com
Ertl, P. et al., J. Med. Chem. 2000, 43: 3714-3717. (molecular property prediction toolkit ) Ro5 violations Absorption as f(PSA, LogP)
• logP (membrane transport connected with fat and water solubility)
• log pK a (influences binding Ki and also logP)
Intestinal and other absorption • % ABS = 109 – 0.345 PSA (good when %ABS > 30 %) (lower PSA, higher absorption) Zao YH et al. Pharm Res 2002, 19, 1446-1457.
Brain Blood Barrier penetration • LogBB = -0.0148 PSA + 0.152 CLogP + 0.139 (to estimate CNS penetration and possible side effects) BB = C-brain / C-blood CNS: logBB > -0.5 (side effects) non CNS: logBB < -1 Other considerations
• despite good druglikeness some compounds should be avoided as drug candidates:
• If contain substructures with known reactive, toxic , mutagenic or teratogenic properties (RCOX, (RCO) 2O, Michael acceptors,
epoxides, -NO 2, -NO, -N3, NH-NH, N=N...)
• bad metabolic parameters , e.g. fast metabolism can quickly destroy the pharmacological activity of the compound (metabolic half life, metabolic clearance should be determined)
• Inhibit antimetabolites (CYP, hERG, P-glycoprotein)