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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 ΔG bind (the binding free energy with H+,K+-ATPase homology model) and experimental pIC50 (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.

Bisabolangelone is the main active ingredient of Angelica polymorpha, which has the good pharmacological activities such as anti-celialgia, anti-dysmenorrhea and anti-gastralgia. In this study, the neuroprotective effect of bisabolangelone against hydrogen peroxide (H2O2)-induced neurotoxicity in human neuroblastoma cells was studied. The binding capacity between bisabolangelone and calcium channel was calculated by molecular docking method, and calcium concentration was detected by the calcium fluorescent probe of Fura-2 AM. The results indicated that bisabolangelone had a good neuroprotective effect on nerve cells by interacting with calcium channels, mainly blocking the voltage-gated calcium channels, suppressing calcium releasing from the calcium store.

Pharmacophore and three-dimensional quantitative structure–activity relationship (3D-QSAR) model of 106 aryl diphenolic azoles as estrogen receptor-β ligands were proposed. The best pharmacophore model, five-site model including two hydrogen bond donors and three aromatic rings, has been established. The biological activity values (pIC50) and classification (active or inactive) of compounds were predicted by 3D-QSAR model. The model correlation coefficient (R 2) is 0.9623. The classification accuracies in predicting for training, test, and total datasets are 97.5, 84.6, and 94.3 %, respectively. The 3D-QSAR model maps revealed that hydrogen bond donor, hydrophobic, and electron-withdrawing fields would be the essential factors for designing new ligands with higher biological activity. The results indicate that the combination of pharmacophore and 3D-QSAR analyses could be a powerful modeling tool for finding novel estrogen receptor-β ligands.

The homology model of human gastric H+/K+-ATPase has been produced based on the template provided by pig gastric H+/K+-ATPase (PDB code: 3IXZ). After molecular mechanics optimization, induced-fit docking simulation between gastric H+/K+-ATPase and bisabolangelone that has significantly inhibition activity of H+/K+-ATPase was performed. The results of ligand docking showed that the binding pocket involves the amino acid residues Asp101, Asp102, Tyr105, Leu106, Val296, Phe297, Met299, Ala300, Tyr764, Tyr767, Leu774, Gly777, Cys778, Ile779, Gln889, Tyr893, and Ile952. The hydrogen bonds are formed between bisabolangelone and the amino acid residues Cys778, Gln889, and Tyr893.