Computational analysis of aza analogues of 2′,5′-bis-O-(tert- butyldimethylsilyl)-β-D-ribofuranosel-3′-spiro-5″(4″- amino-1″,2″-oxathiole-2″,2″-dioxide) (TSAO) as HIV-1 reverse transcriptase inhibitors: Relevance of conformational properties on the inhibitory activity

摘要

We have carried out a theoretical analysis of aza analogues of [2′,5′-bis-O-(tert-butyldimethylsilyl)-β-Dribofuranosyl] -3′-spiro-5″-(4″-amino-l″,2″-oxathiole-2″, 2″-dioxide) by a variety of computational tools, aimed to account for the effect of the endocyclic amino moiety N-2″ on the inhibitory activity against HIV-1. Docking studies suggest that compounds substituted at the N-3 and N-2″ positions present the same binding mode to the [2′,5′- bis-O-(tert-butyldimethylsilyl)-β-D-ribofuranosyl]-3′-spiro-5″- (4″-amino-1′,2″oxathiole-2″,2″-dioxide)thymine prototype, where the endocyclic amino group remains mostly exposed to the solvent. A careful conformational analysis performed through different theoretical levels, from molecular mechanics to high-level quantum mechanical calculations, provides a rationalization based on conformational preferences, which appears as strongly determined by the substitution at N-2″, and on electrostatic effects from the bulk water. © 2006 American Chemical Society.