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The Application of Semiempirical Methods in Drug Design

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The Application of Semiempirical Methods in Drug Design THE APPLICATION OF SEMIEMPIRICAL METHODS IN DRUG DESIGN By MARTIN B. PETERS A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2007 1 c 2007 Martin B. Peters 2 For Jane 3 ACKNOWLEDGMENTS Words cannot describe my Jane. She is everything I can could ask for. She has stood by me even when I left Ireland to pursue my dream of getting my PhD. Thank you honey for your love, support and the sacrifices you have made for us. I thank my mother for always giving me tremendous support and for her words of wisdom and encouragement. I would also like to thank my two brothers, Patrick and Francis, and my two sisters, Marian and Deirdre, for all their encouragement and support. Kennie thank you for giving me the opportunity to work with you; I have truly enjoyed the experience. I would like to express my gratitude to all Merz group members especially Kaushik, Andrew, Ken, Kevin, and Duane for their support and friendship. Also I would like to acknowledge the effort of Mike Weaver who helped by editing this dissertation. 4 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................. 4 LIST OF TABLES ..................................... 8 LIST OF FIGURES .................................... 11 LIST OF ABBREVIATIONS ............................... 15 ABSTRACT ........................................ 19 CHAPTER 1 INTRODUCTION .................................. 21 2 THEORY AND METHODS ............................. 25 2.1 Receptor-Ligand Binding Free Energy ..................... 28 2.2 Computational Drug Design .......................... 30 2.3 Molecular Mechanics .............................. 32 2.4 Quantum Mechanics .............................. 33 2.5 Ligand Based Drug Design ........................... 34 2.5.1 3D-QSAR with QM descriptors .................... 35 2.5.2 Field-based Methods .......................... 36 2.5.3 Spectroscopic 3-D QSAR ........................ 37 2.5.4 Quantum QSAR and Molecular Quantum Similarity ......... 39 2.6 Receptor Based Drug Design .......................... 40 2.7 Semiempirical Divide-And-Conquer Approach ................ 42 2.8 Pairwise Energy Decomposition (PWD) .................... 44 2.9 Quantum Mechanical Charge Models ..................... 46 2.10 Comparative Binding Energy Analysis (COMBINE) ............. 47 2.11 SemiEmpirical Comparative Binding Energy Analysis (SE-COMBINE) .. 48 2.12 Graph Theory .................................. 49 2.13 Statistical Methods ............................... 54 2.14 Metalloproteins ................................. 59 3 MODELING TOOL KIT++ ............................. 67 3.1 Introduction ................................... 67 3.2 Overview .................................... 68 3.2.1 Development ............................... 68 3.2.2 Library Hierarchy ............................ 69 3.2.3 Molecule Library ............................ 70 3.2.4 Graph Library .............................. 77 3.2.5 MM Library ............................... 78 3.2.6 GA Library ............................... 78 5 3.2.7 Statistics Library ............................ 80 3.2.8 Molecular Fragment Library ...................... 80 3.2.9 Parsers Library ............................. 82 3.3 Hybridization, Bond Order and Formal Charge Perception ......... 83 3.4 Ring Perception ................................. 87 3.5 Addition of Hydrogen Atoms to Molecules .................. 92 3.6 Conformational Sampling ........................... 94 3.7 Substructure Searching/ Functionalize .................... 98 3.8 Clique Detection/ Maximum Common Pharmacophore ........... 101 3.9 Superimposition ................................. 102 3.10 Conclusions ................................... 104 4 SEMIFLEXIBLE QUANTUM MECHANICAL ALIGNMENT OF DRUG-LIKE MOLECULES ........................... 106 4.1 Introduction ................................... 106 4.2 Implementation ................................. 110 4.2.1 Ligand Conformational Searching ................... 110 4.2.2 Structural Alignment and Clique Detection .............. 111 4.2.3 Semiempirical Similarity Score ..................... 112 4.3 Results and Discussion ............................. 113 4.3.1 Data Set ................................. 113 4.3.2 Carboxypeptidase A ........................... 117 4.3.3 Glycogen Phosphorylase ........................ 118 4.3.4 Immunoglobin .............................. 119 4.3.5 Streptavidin ............................... 121 4.3.6 Dihydrofolate Reductase ........................ 123 4.3.7 Trypsin .................................. 125 4.3.8 Estrogen Receptor ............................ 128 4.3.9 Peroxisome Proliferator-Activated Receptorγ ............. 131 4.3.10 Human Carbonic Anhydrase II ..................... 132 4.3.11 Thrombin ................................ 136 4.3.12 Elastase ................................. 136 4.3.13 Thermolysin ............................... 140 4.4 Conclusions ................................... 144 5 METAL CLUSTER MOLECULAR MECHANICS PARAMETERIZATION . 146 5.1 Introduction ................................... 146 5.2 Implementation ................................. 148 5.2.1 Equilibrium Bond Lengths and Angles ................ 150 5.2.2 Force Constants ............................. 150 5.2.3 Point Charges .............................. 151 5.3 Zinc AMBER Force Field ........................... 152 5.3.1 Protein Data Bank Survey of Zinc Containing Proteins ....... 154 5.3.2 Tetrahedral Zn Environment Force Field Parameterization ..... 157 6 5.4 Conclusions ................................... 183 6 CONCLUSIONS ................................... 189 APPENDIX A ALGORITHMS .................................... 191 A.1 Subgraph Isomorphism Algorithm ....................... 191 A.2 Maximum Common Pharmacophore ...................... 193 B AMBER GRADIENTS ................................ 194 B.1 Vector Math and Derivatives .......................... 194 B.2 AMBER First Derivatives ........................... 195 B.2.1 Bond ................................... 195 B.2.2 Angle ................................... 196 B.2.3 Dihedral ................................. 197 B.2.4 Electrostatic ............................... 201 B.2.5 van der Waals .............................. 202 C FRAGMENT LIBRARY ............................... 203 C.1 Terminal Fragments ............................... 203 C.2 Two Point Linker Fragments .......................... 208 C.3 Three Point Linker Fragments ......................... 212 C.4 Four Point Linker Fragments .......................... 214 C.5 Five Point Linker Fragments .......................... 216 C.6 Three Membered Ring Fragments ....................... 217 C.7 Four Membered Ring Fragments ........................ 218 C.8 Five Membered Ring Fragments ........................ 219 C.9 Six Membered Ring Fragments ........................ 224 C.10 Greater than Six Membered Ring Fragments ................. 229 C.11 Fused Ring Fragments ............................. 230 REFERENCES ....................................... 237 BIOGRAPHICAL SKETCH ................................ 263 7 LIST OF TABLES Table page 2-1 Correspondence between Graph Theory and Chemical Terminology. ....... 53 3-1 Disulfide Bond Prediction Parameters. ....................... 73 3-2 Meng Atomic Covalent Radii. ............................ 84 3-3 Labute Algorithm Upper Bound Bond Conditions. ................. 85 3-4 Labute Algorithm Atom Hybridization Assignment. ................ 86 3-5 Labute Algorithm Lower Bound Single Bond Lengths. ............... 86 3-6 Labute Algorithm Bond Weights. .......................... 87 3-7 Hydrogen Bond Lengths. ............................... 94 3-8 Hydrogen Bond Angles. ............................... 94 3-9 Hydrogen Bond Dihedrals. .............................. 95 3-10 Dihedral Angles Available based on Bond Type. .................. 95 4-1 Compound Alignment Literature. .......................... 107 4-2 Protein-Ligand Data Set. ............................... 115 4-3 Statistics of CuTieP Performance. .......................... 117 4-4 Carboxypeptidase A Ligand Alignments. ...................... 118 4-5 Glycogen Phosphorylase Ligand Alignments. .................... 120 4-6 Immunoglobin Ligand Alignments .......................... 123 4-7 Streptavidin Ligand Alignments ........................... 125 4-8 Dihydrofolate Reductase Ligand Alignments. .................... 127 4-9 Trypsin Ligand Alignments ............................. 130 4-10 Estrogen Receptor Ligand Alignments. ....................... 132 4-11 PPARγ Ligand Alignments. ............................. 132 4-12 40 Human Carbonic Anhydrase II Inhibitors. .................... 134 4-13 Human Carbonic Anhydrase II Results. ....................... 138 4-14 Thrombin Ligand Alignments ............................ 139 8 4-15 Elastase Ligand Alignments. ............................. 140 4-16 Thermolysin Ligand Alignments. .......................... 142 5-1 Metal Ions in the Protein Data Bank. ........................ 146 5-2 Published Metalloprotein Force Fields Using the Bonded Plus Electrostatics Model. ......................................... 148 5-3 Metal-Donor Bond Target Lengths. ......................... 153 5-4 Ideal Angles Used to Calculate Root Mean Square Deviations for Tetrahedral, Square Planar, Trigonal Bipyramidal, Square Pyramid and Octahedral Geometries. ...................................... 155 5-5 Tetrahedral Zinc Primary Ligating
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