Computational analysis of aza analogues of [2',5'-bis-O-(tert-butyldimethylsilyl)-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 the inhibitory activity.
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.
Soriano
Elena
E
Laboratorio de Resonancia Magnética, Instituto de Investigaciones Biomédicas (CSIC), C/ Arturo Duperier 4, 28029 Madrid, Spain. esoriano@iib.uam.es
Marco-Contelles
José
J
Tomassi
Cyrille
C
Nguyen Van Nhien
Albert
A
Postel
Denis
D
D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D008968:Molecular Conformation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013141:Spiro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology
D018894:Reverse Transcriptase Inhibitors; D013141:Spiro Compounds; C082493:1-(2',5'-bis-O-(tert-butyldimethylsilylribofuranosyl)-3-N-methylthymine)-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide); D054303:HIV Reverse Transcriptase; D013936:Thymidine