title: Computational Study on New Natural Compound Inhibitors of Pyruvate Dehydrogenase Kinases.
abstract: Pyruvate dehydrogenase kinases (PDKs) are key enzymes in glucose metabolism, negatively regulating pyruvate dehyrogenase complex (PDC) activity through phosphorylation. Inhibiting PDKs could upregulate PDC activity and drive cells into more aerobic metabolism. Therefore, PDKs are potential targets for metabolism related diseases, such as cancers and diabetes. In this study, a series of computer-aided virtual screening techniques were utilized to discover potential inhibitors of PDKs. Structure-based screening using Libdock was carried out following by ADME (adsorption, distribution, metabolism, excretion) and toxicity prediction. Molecular docking was used to analyze the binding mechanism between these compounds and PDKs. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding. From the computational results, two novel natural coumarins compounds (ZINC12296427 and ZINC12389251) from the ZINC database were found binding to PDKs with favorable interaction energy and predicted to be non-toxic. Our study provide valuable information of PDK-coumarins binding mechanisms in PDK inhibitor-based drug discovery.
authors.affiliation: College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin, China. zhouxl@jlu.edu.cn.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of MicrobialMetabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China. yushanshan001@aliyun.com.|Jilin Ginseng Academy, Changchun University of Chinese Medicine, Changchun 130000, Jilin, China. yushanshan001@aliyun.com.
authors.forename: Shanshan
authors.initials: S
authors.lastname: Yu
authors.affiliation: College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin, China. sujing@jlu.edu.cn.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: College of Basic Medical Sciences, Jilin University, Changchun 130021, Jilin, China. sunlk@jlu.edu.cn.
authors.forename: Liankun
authors.initials: L
authors.lastname: Sun
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods*; D003374:Coumarins / Q000737:chemistry* / Q000494:pharmacology; D055808:Drug Discovery; D006801:Humans; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D010069:Oxadiazoles / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D013329:Structure-Activity Relationship
chemical_list: D003374:Coumarins; D007211:Indoles; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; C000612159:ZINC12296427; C000612160:ZINC12389251; D017346:Protein Serine-Threonine Kinases
keywords: coumarins; inhibitor; pyruvate dehydrogenase kinase; virtual screening