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Identification of a Putative Binding Site for [2‘,5‘-Bis-O-(tert-butyldimethylsilyl)-β-d-ribofuranosyl]-3‘-spiro-5‘ ‘-(4‘ ‘-amino-1‘ ‘,2‘ ‘-oxathiole-2‘ ‘,2‘ ‘-dioxide)thymine (TSAO) Derivatives at the p51−p66 Interface of HIV-1 Reverse Transcriptase

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journal contribution
posted on 2001-05-05, 00:00 authored by Fátima Rodríguez-Barrios, Carlos Pérez, Esther Lobatón, Sonsoles Velázquez, Cristina Chamorro, Ana San-Félix, María-Jesús Pérez-Pérez, María-José Camarasa, Heidi Pelemans, Jan Balzarini, Federico Gago
A binding site for TSAO-m3T at the interface between the p66 and p51 subunits of HIV-1 reverse transcriptase (RT) and distinct from that of “classical” HIV-1 non-nucleoside inhibitors is proposed. The feasibility of the binding mode was assessed by carrying out nanosecond molecular dynamics simulations for the complexes of TSAO-m3T with reduced models of both the wild-type enzyme and a more sensitive R172A mutant. The molecular model is in agreement with a previous proposal, with known structure−activity and mutagenesis data for this unique class of inhibitors, and also with recent biochemical evidence indicating that TSAO analogues can affect enzyme dimerization. The relative importance of residues involved in dimer formation and TSAO−RT complex stabilization was assessed by a combination of surface area accessibility, molecular mechanics, and continuum electrostatics calculations. A structure-based modification introduced into the lead compound yielded a new derivative with improved antiviral activity.