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Biochem Biophys Res Commun. 2007 Mar 23;354(4):879-84. Epub 2007 Jan 22.

Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: part II. integrase inhibition.

Author information

1
Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA. sylvia.lee-huang@med.nyu.edu

Abstract

We report molecular modeling and functional confirmation of Ole and HT binding to HIV-1 integrase. Docking simulations identified two binding regions for Ole within the integrase active site. Region I encompasses the conserved D64-D116-E152 motif, while region II involves the flexible loop region formed by amino acid residues 140-149. HT, on the other hand, binds to region II. Both Ole and HT exhibit favorable interactions with important amino acid residues through strong H-bonding and van der Waals contacts, predicting integrase inhibition. To test and confirm modeling predictions, we examined the effect of Ole and HT on HIV-1 integrase activities including 3'-processing, strand transfer, and disintegration. Ole and HT exhibit dose-dependent inhibition on all three activities, with EC(50)s in the nanomolar range. These studies demonstrate that molecular modeling of target-ligand interaction coupled with structural-activity analysis should facilitate the design and identification of innovative integrase inhibitors and other therapeutics.

PMID:
17261269
PMCID:
PMC1857318
DOI:
10.1016/j.bbrc.2007.01.058
[Indexed for MEDLINE]
Free PMC Article

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