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Modeling the Binding of Inhibitors/Drugs to the Human Serotonin Transporter Kalyan Immadisetty

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Modeling the Binding of Inhibitors/Drugs to the Human Serotonin Transporter Kalyan Immadisetty Duquesne University Duquesne Scholarship Collection Electronic Theses and Dissertations Spring 2015 Modeling the Binding of Inhibitors/Drugs to the Human Serotonin Transporter Kalyan Immadisetty Follow this and additional works at: https://dsc.duq.edu/etd Recommended Citation Immadisetty, K. (2015). Modeling the Binding of Inhibitors/Drugs to the Human Serotonin Transporter (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/678 This Immediate Access is brought to you for free and open access by Duquesne Scholarship Collection. It has been accepted for inclusion in Electronic Theses and Dissertations by an authorized administrator of Duquesne Scholarship Collection. For more information, please contact [email protected]. MODELING THE BINDING OF INHIBITORS/DRUGS TO THE HUMAN SEROTONIN TRANSPORTER A Dissertation Submitted to the Bayer School of Natural and Environmental Sciences Duquesne University In partial fulfillment of the requirements for the degree of Doctor of Philosophy By Kalyan Immadisetty May 2015 Copyright by Kalyan Immadisetty 2015 MODELING THE BINDING OF INHIBITORS/DRUGS TO THE SEROTONIN TRANSPORTER By Kalyan Immadisetty Approved April 8, and 2015 ________________________________ ________________________________ Jeffry D. Madura, Ph.D. Jeffrey D. Evanseck, Ph.D. Professor of Chemistry and Biochemistry Professor of Chemistry and Biochemistry (Committee Chair) (Committee Member) ________________________________ ________________________________ David W. Seybert, Ph.D. Christopher K. Surratt, Ph.D. Professor of Chemistry and Biochemistry Professor of Pharmacology (Committee Member) Mylan School of Pharmacy (External Reviewer) ________________________________ ________________________________ Philip P. Reeder, Ph.D. Ralph Wheeler, Ph.D. Dean and Professor, Bayer School of Chair, Department of Chemistry and Natural and Environmental Sciences Biochemistry Professor of Chemistry and Biochemistry iii ABSTRACT MODELING THE BINDING OF INHIBITORS/DRUGS TO THE SEROTONIN TRANSPORTER By Kalyan Immadisetty May 2015 Dissertation supervised by Dr. Jeffry D. Madura Human serotonin transporter (hSERT), a membrane protein from the neurotransmitter sodium symporter family, is implicated in depression disorder and has been the primary target of antidepressant discovery research for several decades. Since the currently available antidepressants may cause adverse effects and have several limitations, novel drugs are highly desired. However, the efforts to develop better therapeutics are hampered by the lack of a crystal structure of hSERT. Knowledge of the binding site of the drug and its orientation in the protein is crucial in structure-based drug discovery. We employed a novel computational protocol comprised of active site detection, docking, scoring, molecular dynamics simulations, and absolute binding free energy (ABFE) calculations to elucidate the binding site and the binding mode of a dual hSERT/5HT-1A blocker SSA-426 and our in-house hSERT inhibitor DJLDU-3-79 in iv hSERT. Through this approach, we propose that both of these inhibitors bind in the S1 pocket of hSERT and in a similar orientation. This disproves the earlier hypothesis that both these inhibitors bind in the S2 site; however, we are in agreement with the earlier hypothesis that both of the ligands orient similarly. Further, we resolved the ambiguity in binding energies and binding trends of the tricyclic antidepressant drugs clomipramine, imipramine, and desipramine with leucine transporter (LeuT) (a bacterial homologue of hSERT) through relative binding free energy (RBFE) calculations. Based on our RBFE results, we proposed that clomipramine should have the highest affinity for LeuT, followed by imipramine and desipramine. Finally, to achieve accuracy in binding energy estimations and to perform all CHARMM simulations, we developed CHARMM general force field parameters (CGenFF) for fifteen monoamine transporter ligands. v DEDICATION I dedicate this dissertation to my family for supporting and motivating me throughout. I also dedicate this to my friends who helped me in many ways, especially in the last one year. vi ACKNOWLEDGEMENT I would like to take this opportunity to express my gratitude to my dissertation advisor Dr. Jeffry D. Madura for giving me this wonderful opportunity. I am fortunate to have a legendary person like him as my dissertation advisor. From day one onwards, Dr. Madura encouraged and supported me in every possible way. Thank you for his extra efforts in preparing me for the earlier defenses, despite being busy as the chair of the department. Dr. Madura constantly motivated me to overcome my shortcomings and patiently pushed me towards the target. I am indebted to him for offering me research assistantship for five consecutive years and also for financially supporting me to go to the Chemical Computing Group (CCG) workshop and three ACS national conferences. Dr. Madura gave absolute freedom and constantly encouraged me to figure out problems on my own, which helped me become an independent thinker. Had he not been patient and motivated me I don't think I would have finished my dissertation. I am thankful to my dissertation committee members Dr. David W. Seybert, Dr. Jeffrey D. Evanseck for mentoring and encouraging me through the years. Special thanks to Dr. Christopher K. Surratt, an external committee member and our experimental collaborator. It was a pleasant experience working with Dr. Surratt; I had the opportunity to write a review article with him and learned a lot in that process. He should be specially appreciated for organizing weekly collaboration meetings along with Dr. David Lapinsky and Dr. Michael Cascio. I thank you all for patiently listening to my research presentations and offering your valuable advice and also for clarifying my doubts. These vii meetings are always filled with positive energy and there was not a situation where I was being let down. I sincerely thank Dr. Ralph A. Wheeler for his presence in the weekly joint group meetings and offering his suggestions. Thanks to Dr. Michael Cascio for his input during my original research proposal. I need to express my gratitude to Dr. Sai Pakkala for helping me get this wonderful opportunity to work in Dr. Madura’s lab and also for helping me settle down in Pittsburgh. Many thanks to Dr. Sankar Manepalli for guiding me through the research project in the beginning days. My current and past lab mates, Riley Workman, Emily Benner, Bernadine Jean, Timothy Gaborek, Matt Srnec, Bonnie Merchant, Dr. Ileana Esposito, Dr. Ignacio General, James Thomas, Jimmy Brancho and Marco Acevedo, thank you all for this wonderful experience, it has been a joy working with all of you. I need to specially thank Dr. Tammy Nolan for helpful discussions, offering valuable advice and fresh vegetables from her backyard. I am grateful to Debesai Hailemicael for patiently listening and for supporting and motivating me throughout. Thank you Laura Geffert for many leisure lunches and fun moments. My Indian colleagues at Duquesne, Dr. Dinesh Nath, Dr. Sumangala Shetty, Nageswari Yerravarapu, Rathna Veeramachaneni, Kiran Venna, Dr. Srikanth Singamsetty, Dr. Roheeth Pavana, Dr. Uday Kotreka, Dr. Druk Vyas, Dr. Balasundarreddy Dodda and Dr. Ranganadh Velagelati for making this a memorable experience at Duquesne. Thanks to the administrative staff Amy Stroyne, Sandy Russell, Margaret Cowburn and academic advisor Heather Costello for their assistance in many ways. I also thank Department of Chemistry and Biochemistry and Duquesne University for giving me this wonderful opportunity to pursue my graduate studies and also for supporting me viii in every way possible. Lastly I would like to thank Dr. Philip Reeder, dean of BSNES, for offering me tuition scholarship for spring and fall semesters, 2014. ix TABLE OF CONTENTS Page ABSTRACT ....................................................................................................................... iv DEDICATION ................................................................................................................... vi ACKNOWLEDGEMENT ................................................................................................ vii LIST OF TABLES ............................................................................................................ xv LIST OF FIGURES ....................................................................................................... xviii LIST OF ABBREVIATIONS ......................................................................................... xxii 1. CHAPTER 1 ................................................................................................................ 1 1.1. Introduction....................................................................................................................... 1 1.1.1. Monoamine transporter inhibitors and their therapeutic applications ....................... 2 1.2. Free Energy Methods for Protein-Ligand Interactions ..................................................... 8 1.2.1. Explicit methods ........................................................................................................ 8 1.2.2. Implicit methods ...................................................................................................... 16 1.2.3. Hybrid methods ....................................................................................................... 17 1.3. Free Energy Calculations on MATs ..............................................................................
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