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

Sylvia Lee-Huang, Philip Lin Huang, Dawei Zhang, Jae Wook Lee, Ju Bao, Yongtao Sun, Young Tae Chang, John Zhang, Paul Lee Huang

Research output: Contribution to journalArticle

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 EC50 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.

Original languageEnglish (US)
Pages (from-to)879-884
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume354
Issue number4
DOIs
StatePublished - Mar 23 2007

Fingerprint

HIV Fusion Inhibitors
HIV Integrase Inhibitors
Integrase Inhibitors
Integrases
Molecular modeling
Fusion reactions
Amino Acids
Molecules
Disintegration
Catalytic Domain
Ligands
Processing
p31 integrase protein, Human immunodeficiency virus 1
oleuropein
3,4-dihydroxyphenylethanol
Therapeutics

Keywords

  • AIDS
  • HIV-1
  • HIV-1 integrase inhibitor
  • Hydroxytyrosol (HT)
  • Molecular modeling
  • Natural product
  • Oleuropein (Ole)
  • Olive leaf extract (OLE)
  • Small molecule HIV-1 inhibitors
  • Structure-function

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol : Part II. Integrase inhibition. / Lee-Huang, Sylvia; Huang, Philip Lin; Zhang, Dawei; Lee, Jae Wook; Bao, Ju; Sun, Yongtao; Chang, Young Tae; Zhang, John; Huang, Paul Lee.

In: Biochemical and Biophysical Research Communications, Vol. 354, No. 4, 23.03.2007, p. 879-884.

Research output: Contribution to journalArticle

Lee-Huang, Sylvia ; Huang, Philip Lin ; Zhang, Dawei ; Lee, Jae Wook ; Bao, Ju ; Sun, Yongtao ; Chang, Young Tae ; Zhang, John ; Huang, Paul Lee. / Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol : Part II. Integrase inhibition. In: Biochemical and Biophysical Research Communications. 2007 ; Vol. 354, No. 4. pp. 879-884.
@article{8d6c1b97d31a4b558b87a1f0e7e644fc,
title = "Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol: Part II. Integrase inhibition",
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 EC50 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.",
keywords = "AIDS, HIV-1, HIV-1 integrase inhibitor, Hydroxytyrosol (HT), Molecular modeling, Natural product, Oleuropein (Ole), Olive leaf extract (OLE), Small molecule HIV-1 inhibitors, Structure-function",
author = "Sylvia Lee-Huang and Huang, {Philip Lin} and Dawei Zhang and Lee, {Jae Wook} and Ju Bao and Yongtao Sun and Chang, {Young Tae} and John Zhang and Huang, {Paul Lee}",
year = "2007",
month = "3",
day = "23",
doi = "10.1016/j.bbrc.2007.01.058",
language = "English (US)",
volume = "354",
pages = "879--884",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "4",

}

TY - JOUR

T1 - Discovery of small-molecule HIV-1 fusion and integrase inhibitors oleuropein and hydroxytyrosol

T2 - Part II. Integrase inhibition

AU - Lee-Huang, Sylvia

AU - Huang, Philip Lin

AU - Zhang, Dawei

AU - Lee, Jae Wook

AU - Bao, Ju

AU - Sun, Yongtao

AU - Chang, Young Tae

AU - Zhang, John

AU - Huang, Paul Lee

PY - 2007/3/23

Y1 - 2007/3/23

N2 - 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 EC50 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.

AB - 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 EC50 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.

KW - AIDS

KW - HIV-1

KW - HIV-1 integrase inhibitor

KW - Hydroxytyrosol (HT)

KW - Molecular modeling

KW - Natural product

KW - Oleuropein (Ole)

KW - Olive leaf extract (OLE)

KW - Small molecule HIV-1 inhibitors

KW - Structure-function

UR - http://www.scopus.com/inward/record.url?scp=33846821864&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846821864&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2007.01.058

DO - 10.1016/j.bbrc.2007.01.058

M3 - Article

C2 - 17261269

AN - SCOPUS:33846821864

VL - 354

SP - 879

EP - 884

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 4

ER -