Computational Efforts in Early-Stage Drug Discovery: A Use-Case Describing the Discovery and Optimization of Protease-Activated Receptor 4 Antagonists

Abstract

My graduate work has primarily focused on using computational methods applied to early-stage drug discovery. This has involved method development projects that aim to improve existing computational methods, while also applying these methods towards an active drug discovery campaign. The methods development work has led to several first author publications focused on improvements in score functions for ligand docking protocols and explicit water representation. These projects have also been incorporated into larger consortium publications from the broader research community to provide methods overviews and automated testing for these protocols. The application-based side of my research involves using these computational methods towards early-stage drug discovery against G-protein coupled receptor (GPCR) targets, specifically focused on both high-throughput screening and lead-optimization stages. This work has primarily been used in the discovery and lead-optimization of two novel antagonist series against the protease-activated receptor 4 (PAR4) in heavy collaboration with Drs. Heidi Hamm and Craig Lindsley in the Pharmacology and Chemistry Departments, respectively.