Bioassay driven drug discovery and computer-aided drug design

This dissertation describes the discovery and design of therapeutic small molecules via Bioassay Driven Drug Discovery and Computer-Aided Drug Design. The individual disease states addressed include hepatitis C, glioma, testosterone related or responsive conditions, and obesity/diabetes (Chapter 2, 3, 4, and 5, respectively). The first half of this dissertation (Chapter 2 and 3) describes the discovery of novel, first-in-class ligands to pharmaceutically naive targets. These targets emerged as topical observations in the literature or locally that provided a new therapeutic opportunity. The discovery of cell entry receptors for hepatitis C virus represented new anti-HCV target receptors CD81 (and SRBI), and the discovery by the candidate of a novel and selective antiglioma activity (associated receptor is unknown) represented a new brain cancer target activity. These efforts involved the formulation of bioassays and testing of small molecules for activity against the novel therapeutic targets. The discoveries obtained were the nucleating events for ongoing projects.;This dissertation reports pioneering efforts with regard to discovery of novel templates and preliminary SAR studies for HCV and antiglioma chemotherapeutic agents, and development of innovative AR and β₃ computational models.;The second half of the dissertation describes computer-aided drug design (CADD) applied to already established projects. CADD models were formulated and/or validated to solve problems inherent to the design of ligands for the androgen receptor or the β₃ adrenergic receptor, Chapter 4 and 5, respectively, as well as provide predictions for the glioma project (Chapter 3). The problem inherent to the design of AR ligands was the lack of predictive computational models to provide guidance in the synthesis of higher affinity AR ligands. The problem for the β₃ adrenergic receptor ligand design project was the lack of bioavailability in a series of very potent agonists. The models obtained addressed the project-specific problems and were an improvement over those currently available.