Computational Analysis of Aza Analogues of [2',5'-Bis-O-(tert-butyldimethylsilyl)--D
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- 作者：Elena Soriano ; José ; Marco-Contelles ; Cyrille Tomassi ; Albert Nguyen Van Nhien ; Denis Postel
- 刊名：Journal of Chemical Information and Modeling
- 出版年：2006
- 出版时间：July 2006
- 年：2006
- 卷：46
- 期：4
- 页码：1666 - 1677
- 全文大小：989K
- 年卷期：v.46,no.4(July 2006)
- ISSN：1549-960X
文摘
We have carried out a theoretical analysis of aza analogues of [2',5'-bis-O-(tert-butyldimethylsilyl)-
-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 againstHIV-1. Docking studies suggest that compounds substituted at the N-3 and N-2' ' positions present the samebinding mode to the [2',5'-bis-O-(tert-butyldimethylsilyl)--D-ribofuranosyl]-3'-spiro-5' '-(4' '-amino-1' ',2' '-oxathiole-2' ',2' '-dioxide)thymine prototype, where the endocyclic amino group remains mostly exposed tothe solvent. A careful conformational analysis performed through different theoretical levels, from molecularmechanics to high-level quantum mechanical calculations, provides a rationalization based on conformationalpreferences, which appears as strongly determined by the substitution at N-2' ', and on electrostatic effectsfrom the bulk water.
-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 againstHIV-1. Docking studies suggest that compounds substituted at the N-3 and N-2' ' positions present the samebinding mode to the [2',5'-bis-O-(tert-butyldimethylsilyl)--D-ribofuranosyl]-3'-spiro-5' '-(4' '-amino-1' ',2' '-oxathiole-2' ',2' '-dioxide)thymine prototype, where the endocyclic amino group remains mostly exposed tothe solvent. A careful conformational analysis performed through different theoretical levels, from molecularmechanics to high-level quantum mechanical calculations, provides a rationalization based on conformationalpreferences, which appears as strongly determined by the substitution at N-2' ', and on electrostatic effectsfrom the bulk water.