Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part II. Integrase inhibition
- Department of Biochemistry, New York University School of Medicine, New York, NY 10016 (United States)
- American Biosciences, Boston, MA 02114 (United States)
- Department of Chemistry, New York University, New York, NY 10003 (United States)
- Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114 (United States)
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{sub 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.
- OSTI ID:
- 20979839
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 354, Issue 4; Other Information: DOI: 10.1016/j.bbrc.2007.01.058; PII: S0006-291X(07)00082-4; Copyright (c) 2007 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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