Identification of a putative binding site for [2 ',5 '-bis-O-(tert-butyldimethylsilyl)beta-D-ribofuranosyl]-3 '-spiro-5 ''-(4 ''-amino-1 '',2 ''-oxathiole-2 '',2 ''-dioxide)thymine (TSAO) derivatives at the p51-p66 interfaceof HIV-1 reverse transcriptase

A binding site for TSAO-m(3)T at the interface between the p66 and p51 subu nits of HIV-1 reverse transcriptase (RT) and distinct from that of "classic al" HIV-1 non-nucleoside inhibitors is proposed. The feasibility of the bin ding mode was assessed by carrying out nanosecond molecular dynamics simula tions for the complexes of TSAO-m(3)T with reduced models of both the wildt ype enzyme and a more sensitive R172A mutant. The molecular model is in agr eement with a previous proposal, with known structure-activity and mutagene sis data for this unique class of inhibitors, and also with recent biochemi cal evidence indicating that TSAO analogues can affect enzyme dimerization. The relative importance of residues involved in dimer formation and TSAO-R T complex stabilization was assessed by a combination of surface area acces sibility, molecular mechanics, and continuum electrostatics calculations. A structure-based modification introduced into the lead compound yielded a n ew derivative with improved antiviral activity.