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
Rights & PermissionsPrintExport