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
em Zh
| WPRIM
| ID: wpr-306460
Biblioteca responsável:
WPRO
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>
Texto completo:
1
Índice:
WPRIM
Assunto principal:
Farmacologia
/
Sítios de Ligação
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Anticorpos Anti-HIV
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Testes de Sensibilidade Microbiana
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Proteína gp120 do Envelope de HIV
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Fusão Celular
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Linhagem Celular
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HIV-1
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Fármacos Anti-HIV
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Avaliação Pré-Clínica de Medicamentos
Tipo de estudo:
Diagnostic_studies
/
Screening_studies
Limite:
Humans
Idioma:
Zh
Revista:
Journal of Southern Medical University
Ano de publicação:
2013
Tipo de documento:
Article