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Enhancement of the Synthetic Sprout De Novo Ligand Design Program Knowledge Base

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Enhancement of the Synthetic Sprout De Novo Ligand Design Program Knowledge Base ENHANCEMENT OF THE SYNTHETIC SPROUT DE NOVO LIGAND DESIGN PROGRAM KNOWLEDGE BASE. SPROUT APPLICATION FOR 17β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ENZYME Sari Alho 2005 Laboratory of Organic Chemistry, Department of Chemistry, University of Helsinki, Finland ENHANCEMENT OF THE SYNTHETIC SPROUT DE NOVO LIGAND DESIGN PROGRAM KNOWLEDGE BASE. SPROUT APPLICATION FOR 17β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 ENZYME Sari Alho University of Helsinki Faculty of Science Department of Chemistry Laboratory of Organic Chemistry P.O. Box 55, FIN-00014 University of Helsinki ACADEMIC DISSERTATION To be presented with the permission of the Faculty of Science of the University of Helsinki for public criticism in Auditorium A 110 of the Department of Chemistry, A. I. Virtasen aukio 1, on April 1st, 2005 at 12 o’clock noon Helsinki 2005 ISBN 952-91-6304-5 (paperback) ISBN 952-10-1354-0 (PDF) http://ethesis.helsinki.fi Helsinki 2005 Gummerus Oy 1 CONTENTS ABSTRACT 4 ACKNOWLEDGEMENTS 6 ABBREVIATIONS 8 1. INTRODUCTION 11 1.1 Structure-based drug design 11 1.2 SPROUT and SynSPROUT 15 1.3 Biological background 17 2. AIMS OF THE STUDY 19 3. OVERVIEW OF SPROUT COMPONENT PROGRAM 21 3.1 Survey of de novo ligand design programs 21 3.2 SPROUT 24 3.2.1 Current developments of SPROUT 24 3.2.2 General features 25 3.2.3 CANGAROO 28 3.2.4 HIPPO 30 3.2.4.1 Boundary surface 31 3.2.4.2 HIPPO target sites 32 3.2.4.3 Pharmacophore module 38 3.2.5 ELEFANT 39 3.2.5.1 SPROUT template library 40 3.2.6 SPIDER 43 3.2.6.1 User defined parameters 44 3.2.6.2 Template joining 45 3.2.6.3 The search process 47 3.2.7 ALLIGATOR 48 3.3 SynSPROUT 50 3.3.1 Knowledge base and PATRAN language 51 3.3.1.1 Chemical patterns 51 3.3.1.2 Joining rules 51 3.3.1.3 Other specifications 52 3.3.2 New fragment library 53 2 3.3.3 Differences between Classic and SynSPROUT 53 3.4 Further modelling applications 54 3.4.1 Moloc 54 3.4.2 MacroModel 54 3.4.3 AutoDock 55 3.4.4 eHiTS® 55 3.4.5 SPA-Docking 55 3.4.6 CAESA 56 4. REVIEW OF STEROID HORMONES AND HYDROXYSTEROID DEHYDROGENASES 57 4.1 Structure of the steroid hormones 57 4.2 Physiological effects of estrogens 58 4.3 Estrogen biosynthesis 59 4.4 Hydroxysteroid dehydrogenase family 63 4.4.1 SDR and AKR protein superfamilies 63 4.4.2 Members of the hydroxysteroid dehydrogenase family important for human physiology 65 4.4.2.1 3β-Hydroxysteroid dehydrogenase/ketosteroid isomerase 66 4.4.2.2 11β-Hydroxysteroid dehydrogenase 66 4.4.2.3 3α-Hydroxysteroid dehydrogenase 67 4.4.2.4 20α-Hydroxysteroid dehydrogenase 68 4.4.2.5 Multiple specificities of hydroxysteroid dehydrogenases 69 4.4.3 17β-Hydroxysteroid dehydrogenase/ketosteroid reductase 69 4.4.3.1 Members of the 17βHSD/KSR family 73 4.4.3.2 Crystal structure information of the 17βHSD/KSR in PDB 78 4.4.3.3 Overall description of the 17βHSD/KSR (type 1) enzyme structure 79 4.4.3.4 Ligand-binding domain and the interactions 81 4.4.3.5 Cofactor-binding site 87 4.4.3.6 Reduction mechanism 88 4.4.3.7 Inhibition studies of 17βHSD/KSR enzymes 89 4.4.4 Crystallisation studies of estrogen receptor α and β 91 5. RESULTS AND DISCUSSION 94 3 5.1 Development of SynSPROUT knowledge base 94 5.1.1 1,3-Dipolar cycloaddition reactions 94 5.1.1.1 Azomethine ylides 96 5.1.1.2 Stereochemistry of the 1,3-dipolar cycloaddition reactions 99 5.1.2 Azomethine ylide chemical patterns and joining rules 100 5.2 Inhibitor design for 17βHSD/KSR1 104 5.2.1 Crystal structures selection 104 5.2.1.1 Active site study of estradiol complex 105 5.2.1.2 Active site study of equilin complex 108 5.2.1.3 Active site study of dihydrotestosterone complex 112 5.2.1.4 Active site study of dehydroepiandrosterone complex 115 5.2.1.5 Active site studies of the estrogen receptor α and β 118 5.2.2 Structure generation 119 5.2.2.1 Structure generation for estradiol complex 121 5.2.2.2 Structure generation for equilin complex 125 5.2.2.3 Structure generation for dihydrotestosterone complex 129 5.2.2.4 Structure generation for dehydroepiandrosterone complex 132 5.2.2.5 New structure generation for dihydrotestosterone complex with the latest version of SPROUT 135 5.2.3 Examination of potential inhibitor structures 136 5.2.3.1 Modifications and optimisation studies of the selected structures 137 5.2.3.2 Energy optimisation and further analysis of selected molecules 144 5.2.4 Docking studies 152 5.2.4.1 Docking simulations into the 17βHSD/KSR1 active site 152 5.2.4.2 Docking simulations into the estrogen receptor α and β active sites 155 5.2.5 Retrosynthesis and synthesis plan 156 5.2.6 Retrosynthesis by CAESA 158 6. CONCLUSIONS AND FUTURE PERSPECTIVES 165 7. REFERENCES 167 8. APPENDICES 183 4 ABSTRACT As part of this thesis various de novo ligand design programs are briefly surveyed. The utilization and characteristics of the SPROUT ligand design program are presented in more detail. The thesis also discusses the process which led towards an extension of the knowledge base of the SynSPROUT ligand design program. It was visualized that pyrrolidine moieties might constitute a key structural element of the sought-after 17β-hydroxysteroid dehydrogenase/ketosteroid reductase type 1 enzyme inhibitor candidates. Thus, a literature survey of azomethine ylide reactions, capable of producing pyrrolidine and related ring structures, was carried out in order to be able then to add the information regarding these reactions to the SynSPROUT program’s knowledge base. The text files were written for the knowledge base containing chemical patterns describing functional groups of 1,3-dipoles and dipolarophiles. For eventual addition into the knowledge base, the next step is to develop the ring formation programming language currently lacking in SynSPROUT. A survey of the 17β-hydroxysteroid dehydrogenase/ketosteroid reductase enzyme family is also presented. These enzymes are responsible for the final step of the biosynthesis of the sex hormones. In many cases they also stimulate the proliferation of breast and prostate cancers. Because 17β-hydroxysteroid dehydrogenase/ketosteroid reductase type 1 (17β-HSD/KSR1) enzyme catalyses estrogen synthesis it is an attractive target for structure-based ligand design for the prevention and control of breast tumour growth. The experimental work focused upon the inhibitor ligand design for 17β-HSD/KSR1 enzyme using the SPROUT de novo ligand design program. The three-dimensional crystal structure coordinates of the enzyme type 1 complexed with four different substrates (estradiol, equilin, dihydrotestosterone and dehydroepiandrosterone) have been used for the study. Structure generation of the novel ligand molecule libraries are described step-by-step. Thousands of new molecules were created for the enzyme active site. A set of molecules (64) were selected using SPROUT program’s scoring function and the ALLIGATOR module. Modifications of the functional groups and energy optimisations were carried out for the selected molecules. The interaction results of the optimised molecules were compared with SPROUT information. In silico docking simulations were performed for a promising subset of molecules and the best docking result was also compared with the original molecule generated using SPROUT. Both optimisation and docking simulation results supported the SPROUT generation results. The 5 retrosynthesis and synthetic plan for one new molecule is presented as an example and also the results of retrosynthetic program for the molecule. 6 ACKNOWLEDGEMENTS The experimental work for this thesis was carried out in the Laboratory of Organic Chemistry of the University of Helsinki and the Institute for Computer Applications in the Molecular Science (ICAMS) of the University of Leeds, United Kingdom. I am most grateful to my supervisor, Professor Kristiina Wähälä, for introducing the fascinating world of molecular modelling to me. I particularly appreciate her numerous suggestions and helpful criticism during this work. I am exceedingly grateful to Professor A. Peter Johnson and Dr. Kimmo Vihko for reviewing the manuscript of the thesis and for their helpful comments, and Dr. Louise Fletcher for revising the language of the present manuscript. Sincere thanks to all members at Organic Chemistry Laboratory in Helsinki University. I wish to thank Emeritus Professor Tapio Hase for his constructive comments of the organic chemistry problems and Dr. Jorma Koskimies for his help with molecular modelling problems in the beginning of my studies. Many warm thanks to all former and present members of the Phyto-Syn group at Organic Chemistry Laboratory. I am deeply indebted to Barbara for her endless support and help. Warm thanks are owing to the members of the ICAMS group in Leeds University. Special thanks to Vilmos, Aniko and Krisztina for their help during my work in Leeds University. I would like to thank my friends and former study mates for their support. Thanks are extended to Katariina, Päivi ja Maarit for providing the berth during my stays in Helsinki. I am deeply grateful to my good friends in Leeds especially Sari and Houry with whom I have had many fruitful conversations. I would like to express my deepest gratitude to my parents and siblings for their encouragement during my studies and special thanks to my father for financial support during the last year. Finally a multitude thanks to my fiancé Paul for his support, understanding and love.
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