title: Targeting AMPK signalling pathway with natural medicines for atherosclerosis therapy: an integration of in silico screening and in vitro assay.
abstract: An integration of virtual screening and kinase assay was reported to identify AMPK kinase inhibitors from various natural medicines.The activation of AMP-activated protein kinase (AMPK) signalling pathway plays a central role in the pathologic progression of atherosclerosis (AS). Targeting the AMPK is thus considered as a potential therapeutics to attenuate AS. Here, we report the establishment of a synthetic pipeline that integrates in silico virtual screening and in vitro kinase assay to discover new lead compounds of AMPK inhibitors. The screening is performed against a large-size pool of structurally diverse natural products, from which a number of compounds are inferred as promising candidates, and few of them are further tested in vitro by using a standard kinase assay protocol to determine their inhibitory potency against AMPK. With this scheme we successfully identify five potent AMPK inhibitors with IC50 values at micromolar level. We also examine the structural basis and molecular mechanism of nonbonded interaction network across the modelled complex interface of AMPK kinase domain with a newly identified natural medicine.
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Tiantong
authors.initials: T
authors.lastname: Ou
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Xumin
authors.initials: X
authors.lastname: Hou
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Shaofeng
authors.initials: S
authors.lastname: Guan
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Jinjie
authors.initials: J
authors.lastname: Dai
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Wenzheng
authors.initials: W
authors.lastname: Han
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Ruogu
authors.initials: R
authors.lastname: Li
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Wang
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Xinkai
authors.initials: X
authors.lastname: Qu
authors.affiliation: a Cardiology Department of Shanghai Chest Hospital , Shanghai Jiaotong University , 241 West Huaihai Road, Shanghai 200030 , P.R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D004789:Enzyme Activation; D006801:Humans; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D001688:Biological Products; D047428:Protein Kinase Inhibitors; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; atherosclerosis; inhibitor; natural product