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Refinement of the Docking Component of Virtual Screening for Pparγ Therapeutics Using Pharmacophore Analysis and Molecular Dynamics

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Refinement of the Docking Component of Virtual Screening for PPARγ Therapeutics Using Pharmacophore Analysis and Molecular Dynamics Stephanie Nicole Lewis Dissertation submitted to the faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy In Genetics, Bioinformatics, and Computational Biology David R. Bevan, Chair Josep Bassaganya-Riera Jill Sible Liqing Zhang June 11, 2013 Blacksburg, VA Keywords: Virtual screening, PPARγ, Drug discovery, Molecular docking, Pharmacophore screening, Molecular dynamics Copyright 2013, Stephanie Nicole Lewis Refinement of the Docking Component of Virtual Screening for PPARγ Therapeutics Using Pharmacophore Analysis and Molecular Dynamics Stephanie Nicole Lewis ABSTRACT Exploration of peroxisome proliferator-activated receptor-gamma (PPARγ) as a drug target holds applications for treating a wide variety of chronic inflammation-related diseases. Type 2 diabetes (T2D), which is a metabolic disease influenced by chronic inflammation, is quickly reaching epidemic proportions. Although some treatments are available to control T2D, more efficacious compounds with fewer side effects are in great demand. Drugs targeting PPARγ typically are compounds that function as agonists toward this receptor, which means they bind to and activate the protein. Identifying compounds that bind to PPARγ (i.e. binders) using computational docking methods has proven difficult given the large binding cavity of the protein, which yields a large target area and variations in ligand positions within the binding site. We applied a combined computational and experimental concept for characterizing PPARγ and identifying binders. The goal was to establish a time- and cost-effective way to screen a large, diverse compound database potentially containing natural and synthetic compounds for PPARγ agonists that are more efficacious and safer than currently available T2D treatments. The computational molecular modeling methods used include molecular docking, molecular dynamics, steered molecular dynamics, and structure- and ligand- based pharmacophore modeling. Potential binders identified in the computational component funnel into wet-lab experiments to confirm binding, assess activation, and test preclinical efficacy in a mouse model for T2D and other chronic inflammation diseases. The initial process used provided α-eleostearic acid as a compound that ameliorates inflammatory bowel disease in a pre-clinical trial. Incorporating pharmacophore analyses and binding interaction information improved the method for use with a diverse ligand database of thousands of compounds. The adjusted methods showed enrichment for full agonist binder identification. Identifying lead compounds using our method would be an efficient means of addressing the need for alternative T2D treatments. DEDICATION I would like to dedicate this dissertation to all the people in my life, both family and friends, who have done everything humanly possible to help me achieve my goals. Among those are most notably my mother, Stephanie R. Lewis, my grandmother, Bessie White, my husband, Steve Huff, our son, Ayden James, and my brothers, Darin and Daniel Lewis. Thank you for being my daily cheerleaders, entertainers, and taking pride in everything about me including my shortcomings. To my best friend and soul sister, Adria Markowski, thank you for taking the PhD journey with me, and showing me that greatness can be both dreamed and achieved. Thank you to Dennie Munson for being my mom away from home and my champion in all things academic. Thank you to my advisor, David Bevan, for seeing greatness in me, and allowing a level of freedom and independence that seems far too uncommon, but highly necessary, in graduate level education. Your confidence in me has truly helped my development as a leader, mentor, and scientist. Thank you to my amazing colleagues in the Bevan lab for being exceptional sounding boards for ideas, both great and not so great. Thank you to my graduate committee for constantly challenging my thought process and conclusions, and the PREP/IMSD faculty for facilitating professional guidance. The conversations with each of you have shaped my development as a researcher and guided me toward high-impact scientific thought. Thank you to all the students with whom I have worked while at Virginia Tech. It is through you that I see great potential and promise in the scientific endeavors to come. Lastly, I dedicate this to those who did not believe I could rise to this level of success. Through their lack of faith for various reasons at various times, I have been motivated to exceptional belief in my abilities and myself. iii ACKNOWLEDGEMENTS I would like to acknowledge and thank the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) for funding through the Ruth L. Kirschstein National Research Service Awards for Individual Predoctoral Fellowships to Promote Diversity in Health-Related Research (1F31DK091186-01A1). I would like to acknowledge and thank the VT-PREP and IMSD programs and the faculty of the program for their financial and developmental support. These programs are funded through NIH: Biomedical and Behavioral Sciences Research Training Grant R25 GM072767 (Virginia Tech Initiative to Maximize Student Diversity) and Grant R25 GM066534 (Virginia Tech Post Baccalaureate Research and Education Program). Additional sources responsible for funding of the experimental component were Grant 5R01AT4308 from the National Center for Complementary and Alternative Medicine and The National Institute for Allergy and Infectious Diseases Contract HHSN272201000056C. iv Table of Contents 1 Introduction ................................................................................................................. 1 1.1 Chronic inflammation .......................................................................................... 1 1.1.1 Type 2 diabetes ............................................................................................. 1 1.1.2 Inflammatory bowel disease ......................................................................... 2 1.2 PPARγ .................................................................................................................. 3 1.3 Motivation for dissertation project ....................................................................... 3 1.4 Organization of the dissertation ........................................................................... 4 2 Virtual screening as a technique for PPAR modulator discovery............................... 5 2.1 Abstract ................................................................................................................ 6 2.2 Introduction .......................................................................................................... 7 2.3 Characteristics of PPARγ and the activation process........................................... 7 2.4 Agonists and the ligand-binding domain of PPARγ ............................................ 9 2.5 Docking .............................................................................................................. 12 2.6 Virtual screening ................................................................................................ 13 2.7 Limitations of virtual screening ......................................................................... 14 2.8 Docking and virtual screening successes ........................................................... 15 2.9 Relevance to PPARγ agonist discovery ............................................................. 15 2.10 Future directions ............................................................................................. 16 2.11 Acknowledgements ........................................................................................ 17 3 Dietary -eleostearic acid ameliorates experimental inflammatory bowel disease in mice by activating peroxisome proliferator-activated receptor- ..................................... 18 3.1 Abstract .............................................................................................................. 19 3.2 Introduction ........................................................................................................ 20 3.3 Methods .............................................................................................................. 21 3.3.1 Docking procedure ...................................................................................... 21 3.3.2 Structural model selection: Re-docking component ................................... 22 3.3.3 Structural model selection: Cross-docking component .............................. 22 3.3.4 Small-scale in-house ligand library construction ........................................ 23 3.3.5 Docking analysis for re-docking and cross-docking ................................... 23 3.3.6 Docking analysis for small-scale VS .......................................................... 24 3.3.7 Ligand binding assay .................................................................................. 24 3.3.8 Transfection of RAW 264.7 cells ............................................................... 25 3.3.9 Animal procedures ...................................................................................... 25 3.3.10 Histopathology ...........................................................................................
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