Two Receptor Based Pharmacophore Models for HIV-1 Integrase DKA Inhibitors

Hiv-1 integrase (IN) is an important and validated target for drug design. The diketo acid (DKA) compounds were identified as potent inhibitors for IN. Due to the IN-5citep complex structure has been resolved, it can give hints for IN-DKAs binding mode. A comprehensive receptor based pharmacophore model based on the reasonable binding mode is feasible for developing new and better inhibitors. In this report, 8 effective carbazolone-containing and 8-hydroxy-[1,6] naphthyridine-containing alpha,Gamma- diketo acid inhibitors were docked to IN, respectively. Then, receptor-based pharmacophore models were generated according to the structural constraints of IN and the interactive features between IN and inhibitors. We attempted to refine the obtained pharmacophore models according to the corresponding residues of IN around pharmacophore features. Finally, The common features were obtained by comparing the pharmacophore models obtained above with a pharmacophore model generated based on MK-0518. The common features coexisted in diverse skeleton ligand structures and receptor-ligand interactions indicate the essential interactions between IN and DKA inhibitors reliably. The results obtained above are helpful for us to rationally design and synthesize new potential DKA IN inhibitors.