3D-QSAR studies on 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4- carboxamide derivatives as HIV-1 integrase inhibitors

• Integrase with no cellular equivalent in host is a key enzyme in replication process of retrovirus.
• 3D-QSAR studies were performed on 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide derivatives.
• 3D-QSAR results were verified using molecular docking studies.
• Validated models were used for designing new series of HIV-1 integrase inhibitor.

HIV integrase enzyme is well established potential target for antiretroviral therapy since a decade. Resistance to drugs (Raltegravir and Elvitegravir) used as HIV integrase inhibitors is already been identified and there is an urgent need to discover newer molecules which can overcome this issue. With this aim, ligand based drug design technique, 3D-QSAR, was carried out on a series of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide derivatives as HIV-1 integrase inhibitors. CoMFA and CoMSIA approaches were used for this study. The total dataset of 35 derivatives were divided into training set (28) and test set (7) in 80:20 ratio. In CoMFA model, the cross validated q2 and the non-cross validated r2 value for training set were found as 0.683 and 0.988, respectively; while in CoMSIA model, q2 value was 0.707 and r2 value was 0.989. Further the most active compound 3 was docked into binding site of integrase enzyme using SurFlex-Dock. The CoMFA and CoMSIA contour maps, MOLCAD-generated surface maps of binding site and docking poses were found complimentary with each other in terms of electrostatic, lipophilicity, and hydrogen-bonding potential. These results were used to design novel quinoxaline derivatives as HIV-1 integrase inhibitors which could be explore in future to identify novel HIV-1 integrase inhibitors.