Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: part II. integrase inhibition.
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.
Lee-Huang
Sylvia
S
Department of Biochemistry, New York University School of Medicine, New York, NY 10016, USA. sylvia.lee-huang@med.nyu.edu
Huang
Philip Lin
PL
Zhang
Dawei
D
Lee
Jae Wook
JW
Bao
Ju
J
Sun
Yongtao
Y
Chang
Young-Tae
YT
Zhang
John
J
Huang
Paul Lee
PL
D020134:Catalytic Domain; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D057888:Iridoid Glucosides; D039823:Iridoids; D008958:Models, Molecular; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000737:chemistry; D011714:Pyrans / Q000737:chemistry*; D013329:Structure-Activity Relationship
D019428:HIV Integrase Inhibitors; D057888:Iridoid Glucosides; D039823:Iridoids; D011714:Pyrans; C005975:3,4-dihydroxyphenylethanol; C002769:oleuropein; D019427:HIV Integrase; D010626:Phenylethyl Alcohol