title: Insight into the binding mode between HIV-1 integrase and pyrimidone analogue inhibitors with MD simulation and 3D-QSAR.
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.
authors.affiliation: Shanghai Center for Bioinformation Technology, Shanghai, China.
authors.forename: Songyao
authors.initials: S
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Ye
authors.forename: Dingjue
authors.initials: D
authors.lastname: Ji
authors.forename: Hai-Feng
authors.initials: HF
authors.lastname: Chen
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011744:Pyrimidinones / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D019428:HIV Integrase Inhibitors; D011744:Pyrimidinones; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1