Computational Analysis of Aza Analogues of [2,'5'-Bis-O-(tert-butyldimethylsilyI)-beta-D-ribofuranose]-3'-spiro-5'-(4''-amino-1',2'-oxathiole-2',2'-dioxide) (TSAO) as HIV-1 Reverse Transcriptase Inhibitors:Relevance of Conformational Properties on th

摘要

We have carried out a theoretical analysis of aza analogues of [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro-5"-(4"-amino-1",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)-beta-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.