A 3D QSAR study of a series of HEPT analogues: the influence of conformational mobility on HIV-1 reverse transcriptase inhibition

Journal of Medicinal Chemistry
D B KireevClaude Monneret

Abstract

Quantitative structure-activity relationships (QSAR) have been established for 87 analogues of 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), a potent inhibitor of the HIV-1 reverse transcriptase (RT). Of these 87 nonnucleoside RT inhibitors, 9 novel HEPT analogues were used in the study and the others were taken from the literature. The predictive ability of these relationships has been evaluated using a large set of 54 compounds which were not used to derive the activity model. Descriptors related to the conformational changes were found to be an important factor which underlies RT inhibitory activity in the HEPT series. Indeed, the QSAR model provides evidence concerning the conformational transformations the molecules may undergo during the inhibition process. The established relationships are supplementary to the experimental study on the binding of HEPT type inhibitors to RT by Hopkins et al. (J. Med. Chem. 1996, 39, 1589-1600). The present study suggests a quantitative interpretation of the structure-activity relationships which otherwise cannot be explained within the framework of the crystal inhibitor-protein model. This information is pertinent to the further design of new HEPT type RT inhibitors.

References

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Citations

Jan 25, 2008·Journal of Computer-aided Molecular Design·Robert D Clark
Mar 17, 2004·Bioorganic & Medicinal Chemistry·Shovanlal GayenTarun Jha
Dec 14, 2002·SAR and QSAR in Environmental Research·H BazouiD Zakarya
Mar 29, 2012·SAR and QSAR in Environmental Research·L AkyüzE Yanmaz
Apr 26, 2001·The American Journal of Chinese Medicine·J A WuC S Yuan
Mar 25, 2014·European Journal of Medicinal Chemistry·Alla P ToropovaAleksandar M Veselinović
Nov 18, 2008·Chemical Biology & Drug Design·Zeng LiHai-Feng Chen
Jul 27, 2004·Journal of Chemical Information and Computer Sciences·Jaroslaw PolanskiAndrzej Bak
Jun 25, 2010·Journal of Computational Chemistry·Vali Zare-Shahabadi, Fatemeh Abbasitabar
Feb 26, 2005·Journal of Computer-aided Molecular Design·Robert D Clark, Peter C Fox
Sep 8, 2020·SAR and QSAR in Environmental Research·Y Cañizares-CarmenateJ A Castillo-Garit
Feb 22, 2002·Journal of Chemical Information and Computer Sciences·Brian E Mattioni, Peter C Jurs
Nov 28, 2006·Journal of Chemical Information and Modeling·Jaroslaw PolanskiTomasz Magdziarz
Jun 13, 2000·Journal of Chemical Information and Computer Sciences·G W Kauffman, P C Jurs
Jul 23, 2003·Journal of Chemical Information and Computer Sciences·Latifa DoualiDriss Cherqaoui

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