Abstract
HIV-1 integrase (HIVIN) plays a key role in the replication of the HIV-1 virus and represents an attractive target for anti-HIV drug design. Experimental observation suggests that pyrimidone analogues have potent anti-HIV activity. Then, we modeled an HIVIN catalytic core domain based on the crystal structure of the prototype foamy virus (PFV) integrase. Molecular docking and molecular dynamics simulations were used to investigate the interaction mechanism between pyrimidone analogues and the HIVIN catalytic core domain. MD results suggest that the most active molecule (6K) has more stable hydrogen bonds and hydrophobic contacts than the FDA approved anti-HIV drug Raltegravir. Furthermore, the analogues and Raltegravir might have similar binding modes with HIVIN. Finally, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to construct three dimensional quantitative structure–activity (3D-QSAR) models. Eleven test set compounds which are not included in the training set were used to evaluate these models. The results suggest that these models are robust and have good prediction abilities.
Keywords: HIV-1 integrase, pyrimidone inhibitor, binding mode, CoMFA, CoMSIA, HIV-1 virus, benzene ring, magnesium ion, magnesium ion, electrostatic
Medicinal Chemistry
Title:Insight into the Binding Mode between HIV-1 Integrase and Pyrimidone Analogue Inhibitors with MD Simulation and 3D-QSAR
Volume: 9 Issue: 3
Author(s): Songyao Ma, Wei Ye, Dingjue Ji and Hai-Feng Chen
Affiliation:
Keywords: HIV-1 integrase, pyrimidone inhibitor, binding mode, CoMFA, CoMSIA, HIV-1 virus, benzene ring, magnesium ion, magnesium ion, electrostatic
Abstract: HIV-1 integrase (HIVIN) plays a key role in the replication of the HIV-1 virus and represents an attractive target for anti-HIV drug design. Experimental observation suggests that pyrimidone analogues have potent anti-HIV activity. Then, we modeled an HIVIN catalytic core domain based on the crystal structure of the prototype foamy virus (PFV) integrase. Molecular docking and molecular dynamics simulations were used to investigate the interaction mechanism between pyrimidone analogues and the HIVIN catalytic core domain. MD results suggest that the most active molecule (6K) has more stable hydrogen bonds and hydrophobic contacts than the FDA approved anti-HIV drug Raltegravir. Furthermore, the analogues and Raltegravir might have similar binding modes with HIVIN. Finally, Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) methods were used to construct three dimensional quantitative structure–activity (3D-QSAR) models. Eleven test set compounds which are not included in the training set were used to evaluate these models. The results suggest that these models are robust and have good prediction abilities.
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Cite this article as:
Ma Songyao, Ye Wei, Ji Dingjue and Chen Hai-Feng, Insight into the Binding Mode between HIV-1 Integrase and Pyrimidone Analogue Inhibitors with MD Simulation and 3D-QSAR, Medicinal Chemistry 2013; 9 (3) . https://dx.doi.org/10.2174/1573406411309030013
DOI https://dx.doi.org/10.2174/1573406411309030013 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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