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Virtual screening of small molecular HIV-1 entry inhibitor NC-2 targeting gp120 and its action mechanism / 南方医科大学学报
Journal of Southern Medical University ; (12): 826-831, 2013.
Article in Chinese | WPRIM | ID: wpr-306460
ABSTRACT
<p><b>OBJECTIVE</b>To 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.</p><p><b>METHODS</b>The 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.</p><p><b>RESULTS</b>A 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.</p><p><b>CONCLUSION</b>This 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.</p>
Subject(s)
Full text: Available Index: WPRIM (Western Pacific) Main subject: Pharmacology / Binding Sites / HIV Antibodies / Microbial Sensitivity Tests / HIV Envelope Protein gp120 / Cell Fusion / Cell Line / HIV-1 / Anti-HIV Agents / Drug Evaluation, Preclinical Type of study: Diagnostic study / Screening study Limits: Humans Language: Chinese Journal: Journal of Southern Medical University Year: 2013 Type: Article

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Full text: Available Index: WPRIM (Western Pacific) Main subject: Pharmacology / Binding Sites / HIV Antibodies / Microbial Sensitivity Tests / HIV Envelope Protein gp120 / Cell Fusion / Cell Line / HIV-1 / Anti-HIV Agents / Drug Evaluation, Preclinical Type of study: Diagnostic study / Screening study Limits: Humans Language: Chinese Journal: Journal of Southern Medical University Year: 2013 Type: Article