Fragment-Based Drug Design of Novel HIV-1 Reverse Transcriptase Inhibitors

HIV-1 reverse transcriptase (RT) inhibitors are critical components of antiretroviral therapy (ART) regimens used to control viral load in HIV patients. Previous work identified multiple inhibitory fragments of HIV-RT that bind to a novel allosteric pocket and possess a mechanism of action distinct from that of currently available drugs. This thesis builds upon these studies and applies a fragment-based drug design approach to systematically develop hit compounds into potent inhibitors. Over 120 purified and 180 unpurified compounds were evaluated. Additionally, this thesis describes mutagenesis studies used to assess a possible binding site of these inhibitors.