Docking and 3D-QSAR (quantitative structure activity relationship) studies of flavones, the potent inhibitors of p-glycoprotein targeting the nucleotide binding domain

In order to explore the interactions between flavones and P-gp, in silico methodologies such as docking and 3D-QSAR were performed. CoMFA and CoMSIA analyses were done using ligand based and receptor guided alignment schemes. Validation statistics include leave-one-out cross-validated R(2) (q(2)), internal prediction parameter by progressive scrambling (Q*(2)), external prediction with test set. They show that models derived from this study are quite robust. Ligand based CoMFA (q(2) = 0.747, Q*(2) = 0.639, r(pred)(2) = 0 802) and CoMSIA model (q(2) = 0.810, Q*(2) = 0.676, r(pred)(2) = 0.785) were developed using atom by atom matching. Receptor guided CoMFA (q(2) = 0.712, Q*(2) = 0.497, r(pred)(2) = 0.841) and for CoMSIA (q(2) = 0.805, Q*(2) = 0.589, r(pred)(2) = 0.937) models were developed by docking of highly active flavone into the proposed NBD (nucleotide binding domain) of P-gp. The 3D-QSAR models generated here predicted that hydrophobic and steric parameters are important for activity toward P-gp. Our studies indicate the important amino acid in NBD crucial for binding in accordance with the previous results. This site forms a hydrophobic site. Since flavonoids have potential without toxicity, we propose to inspect this hydrophobic site including Asn1043 and Asp1049 should be considered for future inhibitor design. (C) 2011 Elsevier Masson SAS. All rights reserved.