Combined molecular docking, molecular dynamics simulation and quantitative structure–activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives as potent anti-HIV drugs

• We established several reliable computable models by MLR and SMILES-based methods.
• Several structural features that may help to design potent inhibitors were discussed.
• We used docking to provide useful information for designing potent inhibitors.
• Molecular dynamics simulation was employed to further validate the docking results.
• Docking and dynamics simulation can assist in further studying the mechanism action.

3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine is an antiretroviral agent, which can act against human immunodeficiency virus (HIV) infection, but the mechanism of action of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives remained ambiguous. In this study, multiple linear regression (MLR) was applied to establish a quite reliable model with the squared correlation coefficient (R2) of 0.8079. We also used chemical information descriptors based on the simplified molecular input line entry system (SMILES) to get a better model with R2 of 0.9086 for the training set, and R2 of 0.8031 for the test set. Molecular docking was utilized to provide more useful information between pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives and HIV-1 protease, such as active site, binding mode and important residues. Molecular dynamics simulation was employed to further validate the docking results. This work may lead to a better understanding of the mechanism of action and aid to design novel and more potent anti-HIV drugs.

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