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Application of Molecular Modeling to Drug Discovery and Functional Genomics APPLICATION OF MOLECULAR MODELING TO DRUG DISCOVERY AND FUNCTIONAL GENOMICS A Dissertation Presented By Zhouxi (Josie) Wang To The Department of Chemistry and Chemical Biology in partial fulfillment of the requirements For the degree of Doctor of Philosophy in the field of Chemistry Northeastern University Boston, Massachusetts May, 2012 1 © 2012 Zhouxi Wang ALL RIGHTS RESERVED 2 APPLICATION OF MOLECULAR MODELING TO DRUG DISCOVERY AND FUNCTIONAL GENOMICS By Zhouxi (Josie) Wang ABSTRACT OF DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry in the Department of Chemistry and Chemical Biology in the Graduate School of Northeastern University, Boston, Massachusetts May 2012 3 ABSTRACT Molecular modeling can accelerate and guide drug design and contribute to the understanding of the biochemical functions of gene products. This thesis applies molecular modeling to facilitate the drug design for human African trypanosomiasis and develops a new modeling technique for protein biochemical function annotations. A special technique employed in this work is the prediction of the individual amino acids in protein structures that are involved in ligand interactions; these predicted local interaction sites are used for drug discovery and for the prediction of the biochemical function of proteins of unknown function. Chapter 2 applies molecular modeling to the structure based drug design for human African trypanosomiasis (HAT) at the Aurora kinase -1 target. HAT is a vector borne disease caused by several species of trypanosomes, affecting thousands of people every year. This disease is fatal if untreated. Current therapeutic interventions are unsatisfactory, all with limited efficacy or life-threatening side effects. In humans, Aurora kinase is an important target for cancer therapies. Its homologue from the pathogenic Trypanosoma brucei, Aurora kinase -1 (TbAUK1), is a validated target for therapeutic intervention for trypanosomiasis, providing an opportunity to repurpose human Aurora kinase inhibitors for the development of TbAUK1 inhibitors. We conducted comparative modeling of TbAUK1 and docking studies to help design and prioritize inhibitors based on a series of analogs of the pyrrolopyrazole inhibitor danusertib, currently in clinical trials for cancer. The TbAUK1 model has provided further structure-based insights for design of inhibitor affinity and selectivity. New inhibitors designed using the TbAUK1 homology model showed sub-micromolar inhibition in the T. brucei proliferation assay with 25-fold selectivity over human cells. 4 Chapter 3 describes the application of molecular modeling techniques to investigate other targets for Trypanosomiasis treatment, Trypanosoma brucei phosphodiesterase B1 (TbrPDEB1) and Trypanosoma brucei phosphodiesterase B2 (TbrPDEB2). Homology modeling and docking studies for the inhibitors that are repurposed from human phosphodiesterase 4 (PDE-4) inhibitors help to rationalize the structure-activity relationships for the piclamilast series analogs. The comparison of TbrPDEB1, TbrPDEB2 and human PDE-4 has provided insight for the next generation ligand design. Chapter 4 describes molecular modeling techniques applied to the development of protein function annotation methodology for structural genomics proteins. The Protein Structure Initiative (PSI) has led to significant growth in the number of protein structures. So far, over 11,000 structural genomics (SG) proteins have been deposited in the PDB and most of these SG proteins are of unknown or uncertain function. To bridge the biochemical functions and structures of the proteins, we developed a computational method to facilitate the classification and identification of the function of proteins using the 3D structures as input. A new methodology, Structurally Aligned Local Sites of Activity (SALSA) has been developed for this purpose. This method utilizes two previously developed computational active site predictors, POOL and THEMATICS. As a proof of concept, the enzymes in the concanavalin-A like lectins/glucanases superfamily have been classified according to their biochemical function. The proteins in this superfamily have a similar fold, consisting of a sandwich of 12-14 antiparallel beta strands in two curved sheets. Based on the computationally predicted active site residues and a local structural alignment, the enzymes in this superfamily have been successfully sorted into six functional subgroups and information about the function of SG proteins also has been 5 provided. One SG protein has been found to be correctly annotated and four SG proteins are likely to belong to new functional subgroups. 6 ACKNOWLEDGMENTS I am deeply indebted to my advisor, Prof. Mary Jo Ondrechen, without whom none of my thesis research would have been possible. She gave me tremendous encouragement and support through the years. She gave me the opportunity to work on a variety of projects and encouraged me to explore ideas and work independently. She has not only provided me with scientific training, but has also guided me to be a happier and stronger person. I would also like to express deep and sincere gratitude to my co-advisor Prof. Michael Pollastri for his constant support and patient guidance. His creative, engaging and passionate leadership in the research projects had shown me the way to be a good researcher. I also gratefully acknowledge the countless hours he spent on discussing and networking to help various projects really progress. In addition to my advisors, I would like to thank Prof. Zhaohui Sunny Zhou and Prof. Carla Mattos who have provided valuable input and suggestions to this dissertation. I am honored to have them as my thesis committee members. I could not have completed this dissertation without the support, help, and great friendship from the members of Ondrechen lab and Pollastri lab, including Pengcheng Yin, Ramya Parasuram, Joslynn Lee, Stefan Ochiana, Dr. Srinivas Somarowthu and Dr. Jaeju Ko. It is a pleasure to thank all the faculty, student body and staff members of the Department of Chemistry and Chemical Biology, Northeastern University. Special thanks to Dr. Billy Wu, Dr. Ed Witten, Richard Pumphrey, Jean Harris, and Sheila Magee Beare for all the help and assistance. 7 I also want thank my uncle, Guoliang Wang, aunt, Yonglian Chen and cousin Dr. Sean Wang, who offered me unconditional support and love in my life. I also want to thank my parents, who gave me freedom and love. Finally, I give my sincere acknowledgment to the National Science Foundation (MCB- 0843603 and MCB-1158176) and the National Institutes of Health (R01A1082577 and R15A1082515) for support of this research. 8 TABLE OF CONTENTS ABSTRACT 3 ACKNOWLEDGMENTS .............................................................................................................. 7 TABLE OF CONTENTS ................................................................................................................ 9 LIST OF FIGURES ...................................................................................................................... 11 LIST OF TABLES ........................................................................................................................ 15 CHAPTER 1: INTRODUCTION ............................................................................................ 18 1.1 Homology modeling ....................................................................................................... 20 1.2 Docking ........................................................................................................................... 22 1.3 The application of modeling-docking in drug discovery ................................................ 25 1.4 Human African Trypanosomiasis (HAT) ....................................................................... 26 1.5 Target repurposing .......................................................................................................... 26 1.6 Active site prediction ...................................................................................................... 28 1.7 Thesis Overview ............................................................................................................. 31 1.8 References ....................................................................................................................... 34 CHAPTER 2: IDENTIFICATION OF NEW DRUGS FOR THE TREATMENT OF HUMAN AFRICAN TRYPANOSOMIASIS BASED ON COMPARATIVE MODELING OF TBAUK1 ................................................................................................................................... 41 2.1 Introduction ..................................................................................................................... 43 2.2 Methods ........................................................................................................................... 46 2.3. Results and Discussion .................................................................................................. 51 2.4 Conclusions ..................................................................................................................... 80 2.5 References ....................................................................................................................... 81 9 CHAPTER 3: STRUCTURE-BASED T. BRUCEI DRUG DESIGN USING COMPARATIVE MODELING OF THE PHOSPHODIESTERASE TARGETS TBRPDEB1 AND TBRPDEB2 87 3.1 Introduction ....................................................................................................................
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