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ADP-Ribose) Polymerase-1 Catalytic Pocket Using Autogrow4, a Genetic Algorithm for De Novo Design

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ADP-Ribose) Polymerase-1 Catalytic Pocket Using Autogrow4, a Genetic Algorithm for De Novo Design Targeting the Poly (ADP-Ribose) Polymerase-1 Catalytic Pocket Using AutoGrow4, a Genetic Algorithm for De Novo Design by Jacob Oscar Spiegel Bachelor of Engineering in Biomedical Engineering, State University of New York at Stony Brook, 2013 Submitted to the Graduate Faculty of the Dietrich School of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2020 Committee Page UNIVERSITY OF PITTSBURGH DIETRICH SCHOOL OF ARTS AND SCIENCES This dissertation was presented by Jacob Oscar Spiegel It was defended on March 10, 2020 and approved by Dr. Andrew VanDemark, Associate Professor, Department of Biological Sciences Dr. Jeffrey Lawrence, Professor and Chair, Department of Biological Sciences Dr. Bennett Van Houten, Professor, Department of Pharmacology and Chemical Biology Dissertation Director: Dr. Jacob Durrant, Assistant Professor, Department of Biological Sciences ii Copyright © by Jacob Oscar Spiegel 2020 iii Targeting the Poly (ADP-Ribose) Polymerase-1 Catalytic Pocket Using AutoGrow4, a Genetic Algorithm for De Novo Design Jacob Oscar Spiegel, Ph.D. University of Pittsburgh, 2020 AutoGrow4 is a free and open-source program for de novo drug design that uses a genetic algorithm (GA) to create novel predicted small-molecule ligands for a given protein target without the constraints of a finite, pre-defined virtual library. By leveraging recent computational and cheminformatic advancements, AutoGrow4 is faster, more stable, and more modular than previous versions. Features such as docking-software compatibility, chemical filters, multithreading options, and selection methods have been expanded to support a wide range of user needs. This dissertation will cover the development and validation of AutoGrow4, as well as its application to poly (ADP-ribose) polymerase-1 (PARP-1). PARP-1 is a well-characterized DNA-damage recognition protein, and PARP-1 inhibition is an effective treatment for ovarian and breast cancers that are homologous-recombination (HR) deficient1–5. As a well-studied protein, PARP-1 is also an excellent drug target with which to validate AutoGrow4. Multiple crystallographic structures of PARP-1 bound to various PARP-1 inhibitors (PARPi) serve as positive controls for assessing the quality of AutoGrow4-generated compounds in terms of predicted binding affinity, chemical structure, and predicted protein-ligand interactions. iv This dissertation describes how I (1) generated novel potential PARPi with predicted binding affinities that surpass those of known PARPi; (2) validated AutoGrow4 as a tool for de novo drug design, lead optimization, and hypothesis generation, using PARP-1 as a test target; (3) contributed support to the growing notion that there is a need for HR-deficient cancer chemotherapies that do not rely on the same set of protein-ligand interactions typical of current PARPi; (4) generated novel potential PARPi that are predicted to bind to PARP-1 independent of a post-translational modification that is known to cause PARPi resistance; and (5) generated novel potential PARPi that are predicted to bind a secondary PARP-1 pocket that is distant from the primary catalytic site. v Table of Contents Title Page ........................................................................................................................................ i Committee Page ............................................................................................................................ ii Abstract ......................................................................................................................................... iv Table of Contents ......................................................................................................................... vi List of Tables .............................................................................................................................. xix List of Figures ............................................................................................................................. xxi List of Equations ...................................................................................................................... xxiii List of Appendix JSON Files ................................................................................................... xxiv List of Abbreviations ................................................................................................................ xxv Preface ..................................................................................................................................... xxviii Dedication .................................................................................................................................. xxx 1.0 Introduction ............................................................................................................................. 1 1.1 Biological Background ........................................................................................................ 2 1.1.1 DNA Damage Repair in Humans .................................................................................2 1.1.1.1 Base Excision Repair (BER) .................................................................................. 3 1.1.1.2 Non-Homologous End Joining (NHEJ) ................................................................ 4 1.1.1.3 Homologous Recombination (HR) ........................................................................ 5 1.1.2 PARP-1 Recruits BER and Alt-NHEJ With Poly (ADP)-Ribose Chains .................6 1.1.2.1 ADP-Ribosylation as a Form of DNA Repair Signaling ..................................... 6 vi 1.1.2.2 PARP-1 DNA Damage Recognition and Binding ................................................ 9 1.1.2.3 PARP-1 Catabolizes NAD+ to Perform ADP-Ribosylation ............................. 12 1.1.2.4 PARP-1 Acts as an ADP-Ribosyltransferase and ADP-Ribose Acceptor ....... 16 1.1.2.5 PARP-1 Catalytic Activation is Modulated by Interdomain Interactions ...... 18 1.1.2.6 DNA-Unbinding is Regulated by Interdomain Interactions ............................ 24 1.1.3 PARP-1 Roles in Cancer and Cancer Treatments ....................................................28 1.1.3.1 The Prevalence of and Standard-of-Care Management for HR-Deficient Cancers .............................................................................................................................. 28 1.1.3.2 HR-Deficient Cells and PARPi Sensitivity ......................................................... 30 1.1.3.2.1 HR-Deficient Cells and PARPi Sensitivity: Synthetic Lethality ........... 30 1.1.3.2.2 HR-Deficient Cells and PARPi Sensitivity: Catalytic Inhibition and Trapping ............................................................................................................ 31 1.1.3.3 The Four FDA-Approved PARP-1 Inhibitors (PARPi) ................................... 31 1.1.3.4 PARPi Resistance Mechanisms ........................................................................... 34 1.1.3.4.1 PARPi Resistance Mechanisms: HR Reversion and Increased HR Capacity ............................................................................................................. 34 1.1.3.4.2 PARPi Resistance Mechanisms: Altered NHEJ Capacity ..................... 36 1.1.3.4.3 PARPi Resistance Mechanisms: Corrected Replication Forks ............. 37 1.1.3.4.4 PARPi Resistance Mechanisms: Decreased Intracellular PARPi ........ 37 1.1.3.4.5 PARPi Resistance Mechanisms: Altered PARP-1 Capacity ................. 38 1.1.4 The Current State of the Field: PARP-1 and Pharmaceutical Intervention ..........40 1.2 Computational Methodology ............................................................................................ 41 vii 1.2.1 Genetic Algorithms (GA) ............................................................................................42 1.2.1.1 Search Space and the Fundamentals of Genetic Algorithms (GA) ................. 42 1.2.1.2 Populating a Generation of Solutions ................................................................. 43 1.2.1.3 Fitness .................................................................................................................... 44 1.2.1.4 Ranking and Selection Approaches .................................................................... 45 1.2.1.5 Limitations of Genetic Algorithms (GA)............................................................ 46 1.2.2 Computer-Aided Drug Design (CADD).....................................................................47 1.2.2.1 Categories of CADD Techniques ........................................................................ 48 1.2.2.2 De novo and VS CADD ........................................................................................ 48 1.2.3 Chemical Properties for Selecting Drug-Like Compounds .....................................49 1.2.3.1 Absorption, Distribution, Metabolism, Excretion, and Pharmacokinetics (ADME-PK) ...................................................................................................................... 49 1.2.3.2 Chemical Drug-Likeness Filters ......................................................................... 50 1.2.4 Protein-Ligand Interactions and Protein-Ligand Docking......................................54 1.2.4.1 Models of Protein-Ligand Binding ..................................................................... 56 1.2.4.2 Conformational Sampling ..................................................................................
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