Exploiting the Components Leading to Mutational Resistance in Rigid and Flexible Non‐nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Abstract

Non-nucleoside reverse transcriptase Inhibitors (NNRTIs) are antiretroviral drugs that bind to an allosteric site in HIV reverse transcriptase (RT). NNRTIs are often associated with treatment failure due to emergence of resistance mutations. Nevirapine is a first generation, rigid NNRTI that binds only one conformation in the binding site. Rilpivirine was designed as a flexible diarylpyrimidine that can adapt to multiple mutations in the NNRTI binding site. We have established a computational, structure-based method to predict resistance mutations to NNRTIs and similar compounds in development. The objective of the current study is to examine this approach for 2 types of NNRTIs: rigid and flexible inhibitors. We selected nevirapine and rilpivirine for the analysis and resistance prediction. In our approach, we employed molecular docking and residue scanning to predict resistance to both NNRTIs. Results from residue scanning predicted that the K101P mutation conferred high level resistance to rilpivirine and intermediate-level resistance to nevirapine. These predicted results were further validated through structural analysis, molecular dynamics, and an enzymatic reverse transcription assay. Our results indicate that resistance may be caused by the loss of a salt bridge required for the stability and affinity of the NNRTI. As this is a proof of concept, we believe that our computational and structure-based approach may be used to predict resistance to diverse inhibitors in development. Support or Funding Information This study was supported and funded by my advisor Dr. Kathleen Frey. Superposition of RT (WT) crystal structure 2ZD1 (green) with RT (K101P) model (orange) generated by residue scans in complex with Rilpivirine (gray). Superposition of RT (WT) crystal structure 1VRT (green) with RT (K101P) model (orange) generated by residue scans in complex with Nevirapine (yellow). This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.