Pingry School SMART Team Project: Modeling Current Strategies in HIV‐1 Reverse Transcriptase Inhibitors

Abstract

Pingry School's 2012 S.M.A.R.T (Students Modeling A Research Topic) Team with Eddy Arnold from The Center for Advanced Biotechnology and Medicine (CABM) at Rutgers University who utilized X‐ray crystallography to determine the structure of HIV‐1 reverse transcriptase (HIV‐1 RT) in multiple functional states which led to detailed understanding of multiple nucleoside RT inhibitors (NRTIs) and and the design of non‐nucleoside RT inhibitors (NNRTIs), including two anti‐AIDS drugs. NRTIs inhibit RT by attaching to the dNTP substrate‐binding pocket, while NNRTIs are allosteric inhibitors. Our project models the NRTI and NNRTI inhibition sites on HIV‐1 RT and demonstrates the efficacy of NRTIs in comparison to NNRTIs on various mutations of HIV‐1 RT. Our physical models contrast the binding of NRTIs and NNRTIs to RT. Specifically, we examine the NRTI drug, AZT, and the NNRTI drugs, etravirine and rilpivirine. The latter two have strategic flexibility and their structures “wiggle and jiggle” inside the binding pocket, consequently making it more difficult for a mutated RT to evade resistance. The Pingry S.M.A.R.T. Team used the findings as a basis for the design of a set of three 3‐dimensional models using Jmol and a 3‐dimensional printer to demonstrate the drug‐RT interactions. These models show interactions that reflect the current research of HIV‐1 RT inhibition. Supported by a grant from the NIH‐SEPA.