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Rational Design of Novel BCL2A1 Inhibitors for Treatment of Autoimmune Diseases: an Integration of Virtual Screening, Transcriptomics and Protein Biophysics

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Rational Design of Novel BCL2A1 Inhibitors for Treatment of Autoimmune Diseases: an Integration of Virtual Screening, Transcriptomics and Protein Biophysics Rational Design of Novel BCL2A1 Inhibitors for Treatment of Autoimmune Diseases: An Integration of Virtual Screening, Transcriptomics and Protein Biophysics A Dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Doctor of Philosophy In the Department of Molecular Genetics, Biochemistry and Microbiology of the College of Medicine By Alexander Thorman B.S./B.A. Miami University 2012 Committee Chair: Jaroslaw Meller, Ph.D. Abstract The balance between cell survival and apoptosis is critical to the modulation of immune responses and misregulation of this balance often mediates diseases such as intrauterine inflammation, rheumatoid arthritis and cancer. The pro-survival proteins of the BCL2-family mediate a pro-survival phenotype through sequestration of the BH3-domain peptides that act as sensitizers to Bax and Bak, which serve as the cell executioners, resulting in mitochondrial outer membrane permeability. This dissertation deals with the design of small molecule inhibitors of BCL2A1 (A1), which has been implicated in a wide array of diseases ranging from autoimmunity resulting in pre-term birth to chemotherapeutic resistance in cancer. To date, no inhibitors specific to A1 have been identified and most that target the BCL2 protein family are unable to effectively block A1 activity. The strategy employed uses a range of approaches for the rational discovery of A1-BH3 interface inhibitors. Structure-informed or rational design of small molecules that are predicted to interact with A1 at the interface, thus sterically blocking BH3 peptides from binding, presents an opportunity to demonstrate how disrupting critical protein-protein interactions may be used to drive protection from autoimmunity, as well as blocking of a compensatory pro-survival mechanism in cancers treated with pro-apoptotic drugs. Virtual screening is first employed to identify candidate small molecules predicted to bind A1, followed by in vitro approaches for biophysical characterization of the binding and activity of candidate inhibitors. Using a multi-stage virtual screening protocol coupled with experimental validation of top ranking candidates resulted in a reduction from 90,086 small ii molecules to 13 that showed significant activity in vitro. These initial lead compounds lay the foundation for developing more specific and sensitive drugs targeting A1. In addition to virtual screening, an alternative, approach to drug discovery that combines cheminformatics and Omics approaches has been developed and applied to identify putative inhibitors of the A1-BH3 interaction. This new approach, dubbed connectivity enhanced Structure-Activity Relation (ceSAR), combines chemical similarity with the analysis of the connectivity between expression signatures of genetic and chemical perturbations generated by the LINCS consortium. Specifically, candidate inhibitors with transcriptional signatures concordant to those of genetic knockdown-induced loss of function of the target protein signature are identified using the iLINCS server. Such identified candidates are expected to interact with the protein target, or another pathway-member up- or down-stream of the target protein, driving a similar transcriptional change to a knockdown of the target of interest. Chemical similarity is then utilized to cluster candidate compounds, identifying distinct structural classes, potentially targeting distinct proteins within the pathway of interest, and representatives of each cluster are used as a starting point for screening in vitro. As part of this dissertation, a new bioinformatics tool that enables ceSAR analysis, dubbed Sig2Lead, has been developed in collaboration with other members of the group and made available to the community as an R Shiny application. The results obtained through using the Sig2Lead application implementing this method demonstrate that it can be combined with virtual docking to provide further enrichment of small molecule libraries. iii iv Author Acknowledgements Over the years, my family has been supportive of everything to which I have set myself. My parents have encouraged my pursuit of knowledge and driven me to aspire to make the most I can of myself. My brother has always pushed me to study harder and learn as much as I can to keep up with him, allowing us both to grow. My grandmother has always been closely involved in my life and supported me through school, encouraging me to hone my skills even from a young age. Without my family, I could not have made it to where I am today. I would like to acknowledge my mentors over the past several years for all of their support and guidance in my scientific career. Andy and Jarek have driven me to be an effective multi-disciplinary researcher and I would not be the scientist I am today without their valuable insights and discussions over the past several years. This work has been a hugely collaborative effort and it took the training and efforts of my mentors to really allow me to develop a wide skillset. I hope to remember all of the valuable advice they have provided me with for the rest of my career. Finally, I would like to dedicate my efforts to my amazing wife. Her support has been constant and needed through all of the ups and downs of both my scientific career and my life. She was there when I started my graduate studies, and has been there for me every day since. Her support has sculpted me into the person I am and her encouragement has helped to get me to this point. Thank you to everyone that has been a part of the adventure that is my life. v Table of Contents Rational Design of Novel BCL2A1 Inhibitors for Treatment of Autoimmune Diseases: An Integration of Virtual Screening, Transcriptomics and Protein Biophysics ................................... 1 Abstract ........................................................................................................................................... ii Author Acknowledgements ............................................................................................................ v Table of Contents ........................................................................................................................... vi Table and Figure List ..................................................................................................................... xi Chapter I: Approaches to Rational Design of Novel Small Molecule Inhibitors ........................... 1 Introduction ................................................................................................................................. 2 Disease Association..................................................................................................................... 2 Structure-Informed Design .......................................................................................................... 4 Virtual Screening for Drug Candidates ....................................................................................... 7 Rigid-Body Docking ............................................................................................................... 8 Flexible Docking ................................................................................................................... 11 Interpreting Results of Virtual Screens ................................................................................. 12 Genomics Screening ............................................................................................................. 13 Tanimoto Coefficient for Comparing Structurally Similar Compounds ................................... 15 Fragment Based Screening ........................................................................................................ 19 Peptide Mimetics ....................................................................................................................... 20 vi Chapter II: Rational Design of BCL2A1 Inhibitors ...................................................................... 22 Abstract ..................................................................................................................................... 23 Introduction ............................................................................................................................... 23 Methods ..................................................................................................................................... 28 In silico Docking ................................................................................................................... 28 Protein Expression/Purification ............................................................................................ 29 Thermal Shift Assay ............................................................................................................. 29 Fluorescence Polarization Assay .......................................................................................... 30 LINCS gene expression analysis .......................................................................................... 30 Cell Assays............................................................................................................................ 31 Results ....................................................................................................................................... 31 Discussion ................................................................................................................................
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