title: Aldehyde Oxidase Mediated Metabolism in Drug-like Molecules: A Combined Computational and Experimental Study.
abstract: Aldehyde oxidase (AOX) is an important drug-metabolizing enzyme. However, the current in vitro models for evaluating AOX metabolism are sometimes misleading, and preclinical animal models generally fail to predict human AOX-mediated metabolism. In this study, we report a combined computational and experimental investigation of drug-like molecules that are potential aldehyde oxidase substrates, of which multiple sites of metabolism (SOMs) mediated by AOX and their preferences for the reaction can be unambiguously identified. In addition, the proposed strategy was used to evaluate the metabolism of newly designed c-Met inhibitors, and a success switch-off of AOX metabolism was observed. Overall, this study provide useful information to guide lead optimization and drug discovery based on AOX-mediated metabolism.
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Yulan
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Xing
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.|University of Chinese Academy of Sciences , No. 19A Yuquan Road, Beijing 100049, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Dafang
authors.initials: D
authors.lastname: Zhong
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Luo
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Mingyue
authors.identifier: 0000-0002-3323-3092
authors.initials: M
authors.lastname: Zheng
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Pan
authors.identifier: 0000-0003-2974-7389
authors.initials: P
authors.lastname: Deng
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences , Shanghai 201203, China.
authors.forename: Xiaoyan
authors.identifier: 0000-0002-6559-8627
authors.initials: X
authors.lastname: Chen
mesh_terms: D042931:Aldehyde Oxidase / Q000378:metabolism*; D055808:Drug Discovery; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors; D013045:Species Specificity
chemical_list: D004364:Pharmaceutical Preparations; D042931:Aldehyde Oxidase; D019859:Proto-Oncogene Proteins c-met