Insight into the molecular mechanism of P-glycoprotein mediated drug toxicity induced by bioflavonoids: an integrated computational approach

Abstract In this work, molecular docking, pharmacophore modeling and molecular dynamics (MD) simulation were rendered for the mouse P-glycoprotein (P-gp) (code: 4Q9H) and bioflavonoids; amorphigenin, chrysin, epigallocatechin, formononetin and rotenone including a positive control; verapamil to identify protein–ligand interaction features including binding affinities, interaction characteristics, hot-spot amino acid residues and complex stabilities. These flavonoids occupied the same binding site with high binding affinities and shared the same key residues for their binding interactions and the binding region of the flavonoids was revealed that overlapped the ATP binding region with hydrophobic and hydrophilic interactions suggesting a competitive inhibition mechanism of the compounds. Root mean square deviations (RMSDs) analysis of MD trajectories of the protein–ligand complexes and NBD2 residues, and ligands pointed out these residues were stable throughout the duration of MD simulations. Thus, the applied preliminary structure-based molecular modeling approach of interactions between NBD2 and flavonoids may be gainful to realize the intimate inhibition mechanism of P-gp at NBD2 level and on the basis of the obtained data, it can be concluded that these bioflavonoids have the potential to cause herb–drug interactions or be used as lead molecules for the inhibition of P-gp (as anti-multidrug resistance agents) via the NBD2 blocking mechanism in future.