Virtual screening of small molecular HIV-1 entry inhibitor NC-2 targeting gp120 and its action mechanism.
- Author:
Heng DUAN
1
;
Yuqin WANG
;
Deshou SONG
;
Zhipeng CHEN
;
Jiayin QIU
;
Lu LU
;
Shibo JIANG
;
Shuwen LIU
;
Suiyi TAN
Author Information
- Publication Type:Journal Article
- MeSH: Anti-HIV Agents; pharmacology; Antibodies, Monoclonal; pharmacology; Antibodies, Neutralizing; pharmacology; Binding Sites; Cell Fusion; Cell Line; Drug Discovery; Drug Evaluation, Preclinical; HIV Antibodies; pharmacology; HIV Envelope Protein gp120; antagonists & inhibitors; HIV-1; drug effects; Humans; Microbial Sensitivity Tests
- From: Journal of Southern Medical University 2013;33(6):826-831
- CountryChina
- Language:Chinese
-
Abstract:
OBJECTIVETo screen the HIV-1 entry inhibitors targeting HIV-1 gp120 from the IBS natural product database by virtual screening based on the binding mode of the neutralizing antibody VRC01 with HIV-1 gp120 and investigate the anti-viral activities of the inhibitors and their action mechanisms.
METHODSThe binding interaction of the candidate molecules binding gp120 and changes of the binding free energy were analyzed by MM-PBSA calculation. The anti-HIV-1 activities of the tested compounds were detected by HIV-1 pseudotyped virus, laboratory-adapted HIV-1 and a cell-cell fusion assay. The cytotoxicity of the studied molecules was examined by XTT colorimetric assay. The mechanisms of the anti-viral activities of the candidate molecules were analyzed using enzyme-linked immunosorbent assay.
RESULTSA total of 19 molecules with distinct reduction of the binding free energy after binding with gp120 were screened from 40000 molecules. Among them, NC-2 showed anti-HIV-1 activities against HIV-1 pseudotyped virus and laboratory-adapted HIV-1, and was capable of blocking HIV-1 envelope-mediated cell-cell fusion. The IC50 of NC-2 for inhibiting HIV-1IIIB and pseudotyped HIV-1JRFL infection were 1.95∓0.44 µmol/L and 10.58∓0.13 µmol/L, respectively. The results of ELISA suggested that NC-2 could inhibit the binding of HIV-1 gp120 to CD4 without blocking the formation of gp41 six-helix bundle in vitro.
CONCLUSIONThis computer-based virtual screening method can be used to screen HIV-1 entry inhibitors targeting gp120. Using this virtual screening approach combined with anti-viral activity screening, we obtained a potent HIV-1 entry inhibitor NC-2 with novel structure.