Pharmacophore modeling and 3D-QSAR studies of galloyl benzamides as potent P-gp inhibitors

摘要

P-gp transporter regulates key ADME of drugs in MDR condition. In the present work, a pharmacophore-based 3D-QSAR model was generated for a series of galloyl benzamides analogs possessing P-gp inhibitory activity. Developed pharmacophore model contains two hydrogen-bond acceptors (A), one hydrophobic (H), one hydrogen-bond donor (D) and two aromatic rings (R). These are crucial molecular fingerprints which predict binding efficacy of high-affinity and low-affinity ligands to the P-gp efflux pump. These pharmacophoric features point toward key structural requirements of galloyl benzamides for potent P-gp inhibition. Furthermore, a biological correlation 3D-QSAR variants and functional fingerprints of P-gp responsible for the receptor binding were observed. Alignment of the developed model with P-gp crystal structure indicated importance of A2 and A4 H-bond acceptor sites, which are involved in the important interactions with Glu530 and His690 residues of the active site. Excellent statistical results of QSAR model such as good correlation coefficient (r (2) > 0.95), higher F value (F > 205) and excellent predictive power (Q (2) > 0.6) with low standard deviation (SD < 0.2) strongly suggest that the developed model is good for the future prediction of P-gp inhibitory activity of new galloyl benzamide analogs.