title: Design, synthesis and biological evaluation of bisabolangelone oxime derivatives as potassium-competitive acid blockers (P-CABs).
abstract: With the aim of searching novel P-CABs, seven bisabolangelone oxime derivatives were designed, synthesized, characterized and evaluated the H(+),K(+)-ATPase inhibitory activities guided by computer aided drug design methods. The binding free energy calculations were in good agreement with the experiment results with the correlation coefficient R of -0.9104 between ΔGbind and pIC50 of ligands. Compound 5 exhibited the best inhibitory activity (pIC50=6.36) and most favorable binding free energy (ΔGbind=-47.67 kcal/mol) than other derivatives. The binding sites of these compounds were found to be the hydrophobic substituted groups with the Cys813 residue by the decomposed binding free energy analysis.
authors.affiliation: Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, PR China.
authors.forename: Nian-Yu
authors.initials: NY
authors.lastname: Huang
authors.affiliation: Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, PR China.
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Wang
authors.affiliation: Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, PR China. Electronic address: luohuajun@21cn.com.
authors.forename: Hua-Jun
authors.initials: HJ
authors.lastname: Luo
authors.affiliation: Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, PR China.
authors.forename: Jun-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Reaction Dynamics, Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Science, 457 Zhongshan Road, Dalian 116023, PR China.
authors.forename: Wei-Qiao
authors.initials: WQ
authors.lastname: Deng
authors.affiliation: Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China Three Gorges University, Yichang 443002, PR China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
mesh_terms: D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D017506:H(+)-K(+)-Exchanging ATPase / Q000187:drug effects*; D010091:Oximes / Q000737:chemistry; D011188:Potassium / Q000378:metabolism*; D012717:Sesquiterpenes / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D010091:Oximes; D012717:Sesquiterpenes; C455067:bisabolangelone; D017506:H(+)-K(+)-Exchanging ATPase; D011188:Potassium
keywords: Bisabolangelone; Drug rational design; H(+),K(+)-ATPase inhibitory activities; P-CABs; Synthesis