Molecular docking, binding free energy analysis, and biological evaluation of bisabolonalone hydrazone carboxamides as H + ,K + -ATPase reversible inhibitors

The interaction mechanisms of a series of bisabolonalone hydrazone carboxamides as H + ,K + -ATPase reversible inhibitors were studied by molecular docking, QM/MM calculation, and MM/GBSA binding free energy analysis methods. The correlation coefficient, R , between calculated Δ G bind (the binding free energy with H + ,K + -ATPase homology model) and experimental pIC 50 (negative logarithms of 50% inhibition concentration) of ligands is −0.9386. A suitable molecular volume of ligand is needed to dock into the whole binding pocket, which includes Gln127–Leu141 in the loop of TM1–TM2; Arg328–Ala335 in the loop of TM4; Tyr799–Thr815 in the loop of TM5–TM6; Trp899–Phe917 in the loop of TM7–TM8; Leu921–Tyr928 in the loop of TM8; and Asn986–Asn989 in the loop of TM9–TM10. By the decomposed energy comparisons of residues in binding sites, the naphthyl group substituting benzene ring in bisabolonalone hydrazone carboxamides could increase the hydrophobic interaction with Cys813, which is a very important binding site for enhancing the inhibition activity. In addition, Asp137 is another key residue binding with ligand through the hydrogen bond and electrostatic interactions. The results of this analysis could help in further rational design of novel H + ,K + -ATPase reversible inhibitors.