University of South Florida Scholar Commons Graduate Theses and Dissertations Graduate School 4-15-2015 Development and application of web-based open source drug discovery platforms Yuri Pevzner University of South Florida, [email protected] Follow this and additional works at: https://scholarcommons.usf.edu/etd Part of the Chemistry Commons Scholar Commons Citation Pevzner, Yuri, "Development and application of web-based open source drug discovery platforms" (2015). Graduate Theses and Dissertations. https://scholarcommons.usf.edu/etd/5550 This Dissertation is brought to you for free and open access by the Graduate School at Scholar Commons. It has been accepted for inclusion in Graduate Theses and Dissertations by an authorized administrator of Scholar Commons. For more information, please contact [email protected]. Development and Application of Web-Based Open Source Drug Discovery Platforms by Yuri Pevzner A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry with a concentration in Computational Chemistry Department of Chemistry College of Arts and Sciences University of South Florida Co-Major Professor: Henry Lee Woodcock, Ph.D. Co-Major Professor: Wayne C. Guida, Ph.D. Brian Space, Ph.D. Kenyon G. Daniel, Ph.D. Date of Approval: April 15, 2015 Keywords: CADD, Docking, Virtual Target Screening, CHARMMing Copyright © 2015, Yuri Pevzner DEDICATION I dedicate this work to my mother. Although many people have been instrumental in helping me in this achievement, she alone has seen me through the entire journey that has culminated in this work. From filling my childhood with love and happiness, to giving much needed guidance and encouragement to the developing individual, to having complete faith and confidence in every step I’ve taken since, she has been there. Knowingly or otherwise, she has instilled in me every trait that I value about myself, every trait that defines who I am. Mom, I want to thank you for being there through time and distance, thank you for making home the warm and welcoming place it has always been. Thank you for being my dearest friend. Happy birthday mom, this one is for you! ACKNOWLEDGMENTS I would like to thank my major advisors Dr. H. Lee Woodcock and Dr. Wayne C. Guida. Dr. Woodcock’s energy and infectious excitement about science was what had helped me stay productive and enthusiastic about my work throughout the long and arduous years of studies. Dr. Guida’s wisdom and valuable guidance will serve me well for many years, as in my eyes, he has always been an epitome of a scientist and a teacher. I would also like to thank Dr. Brian Space and Dr. Kenyon G. Daniel. Dr. Space for taking his time and patience to teach me the most important concepts of the physics of chemistry and giving me the tools and the confidence needed to navigate the waters of science. Dr. Daniel for instilling into me the appreciation for biology and, most importantly, for having a much appreciated faith in my scientific abilities and decisions. I would also like to thank the University of South Florida department of chemistry. The faculty and students that have helped create fun and stimulating environment. The administrative staff, in particular Ms. Adrienne McCain, for helping me navigate the administrative requirements, staying on track with the program and, finally, graduating. TABLE OF CONTENTS List of Tables ................................................................................................................................. iii List of Figures ................................................................................................................................ iv Abstract .......................................................................................................................................... vi Chapter One: Introduction ...............................................................................................................1 The Need for Web-Based Open Source Drug Discovery Platforms....................................1 Challenges of Open Source Projects ....................................................................................4 List of References ................................................................................................................7 Chapter Two: Development of the CHARMMing Web User Interface as a Platform for Computer-Aided Drug Design ....................................................................................................9 Note to Reader .....................................................................................................................9 CHARMM Interface and Graphics Platform .......................................................................9 Fragment-Based Docking Protocol in CHARMMing .......................................................11 Implementation Details ..........................................................................................11 Target Preparation ......................................................................................11 Compound Library and Ligand Upload .....................................................11 Binding Site Definition ..............................................................................12 Docking Protocol .......................................................................................15 Job Submission and Monitoring ................................................................19 Performance and Local Execution .............................................................19 Results and Discussion ..........................................................................................22 Conclusion .............................................................................................................26 Acknowledgments..................................................................................................27 List of References ..............................................................................................................28 Chapter Three: Development and Application of the Virtual Target Screening Protocol .............33 Development of the Virtual Target Screening Server ........................................................33 Methodology Background .....................................................................................33 VTS Protocol .........................................................................................................34 VTS Web-Based Interface .....................................................................................35 Application of VTS to Identify Protein Targets of Natural Products in Drug Discovery .38 Natural Products and VTS .....................................................................................38 Materials and Methods ...........................................................................................39 Virtual Compound Libraries ......................................................................39 Ligand Preparation .....................................................................................40 i Virtual Target Screening ............................................................................41 Hardware ....................................................................................................41 Graphics and Modeling ..............................................................................42 Results ....................................................................................................................42 VTS on Natural Products ...........................................................................42 VTS on CDDI Natural Products ................................................................45 Discussion ..............................................................................................................48 Conclusion .............................................................................................................53 Using Molecular Modeling, Chemo- and Bioinformatics to Search for Biomolecular Targets of Vitamin E δ-tocotrienol ..............................................................................53 Introduction ............................................................................................................53 Methods..................................................................................................................57 VEDT Preparation .....................................................................................57 Virtual Target Screening ............................................................................57 PharmMapper .............................................................................................57 PASS (Prediction of Activity Spectra of Substances) ...............................58 ProBiS (Protein Binding Site Detection) ...................................................59 Results ....................................................................................................................59 Discussion ..............................................................................................................64 Consensus between Computational Studies...............................................64 Consistency with Experimental Data .........................................................65 List of References ..............................................................................................................66