1. Targeting AMPK signalling pathway with natural medicines for atherosclerosis therapy: an integration of in silico screening and in vitro assay
- Author
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Min Zhang, Shaofeng Guan, Xin-Kai Qu, Ruo-Gu Li, Tiantong Ou, Xu-Min Hou, Wenzheng Han, Jinjie Dai, and Wenxia Wang
- Subjects
0301 basic medicine ,In silico ,Plant Science ,AMP-Activated Protein Kinases ,Biochemistry ,Analytical Chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,AMP-activated protein kinase ,Drug Discovery ,Animals ,Humans ,Computer Simulation ,Protein Interaction Domains and Motifs ,Molecular Targeted Therapy ,Protein kinase A ,Protein Kinase Inhibitors ,Biological Products ,Virtual screening ,Natural product ,biology ,Kinase ,Organic Chemistry ,AMPK ,Atherosclerosis ,Hedgehog signaling pathway ,Cell biology ,Enzyme Activation ,Molecular Docking Simulation ,030104 developmental biology ,chemistry ,biology.protein ,Signal Transduction - 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.
- Published
- 2015