title: Discovery of Cdc25A Lead Inhibitors with a Novel Chemotype by Virtual Screening: Application of Pharmacophore Modeling Based on a Training Set with a Limited Number of Unique Components.
abstract: Cdc25 phosphatase was studied as an attractive target for cancer therapy. Multiple pharmacophore models with the unique core features of classic quinone inhibitors and those of novel inhibitors were used to discover a novel lead inhibitor. A total of 21 compounds with qualified physical properties were screened from the Maybridge HitFinder database containing 14 400 compounds by pharmacophore models. Four compounds were found to inhibit Cdc25A activity by more than 50 % at a concentration of 100 μm. Among these compounds, KM10389 (N-{2-[(furan-2-ylmethyl)thio]ethyl}-2-[(4-hydroxy-6-propylpyrimidin-2-yl)thio]acetamide) showed high inhibitory activity with an IC50value of 7.9 μm. Selective cytotoxicity toward HeLa cells was observed with an IC50value of 66.3 μm, whereas the IC50value for HEK293 cells was higher than 100 μm. Blocking of the G1/S transition was also observed for HeLa cells in the presence of the compound by increasing the G1 phase by 16.15 %. Together with compounds HTS02435 and HTS01205, a novel lead inhibitor structure was identified and analyzed by a molecular docking study. The implication of virtual screening by using different pharmacophore models representing the different features is fully discussed.
authors.affiliation: Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, University of Sciences and Technology of China, Hefei, 230027, P.R. China.|State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P.R. China.
authors.forename: Yu-Shu
authors.initials: YS
authors.lastname: Ge
authors.affiliation: Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, University of Sciences and Technology of China, Hefei, 230027, P.R. China.
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Han
authors.affiliation: Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, University of Sciences and Technology of China, Hefei, 230027, P.R. China.
authors.forename: Wenxiu
authors.initials: W
authors.lastname: Duan
authors.affiliation: State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P.R. China.
authors.forename: Jia-Qi
authors.initials: JQ
authors.lastname: Zhang
authors.affiliation: Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, University of Sciences and Technology of China, Hefei, 230027, P.R. China.
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.affiliation: Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, University of Sciences and Technology of China, Hefei, 230027, P.R. China.
authors.forename: Jia-Jia
authors.initials: JJ
authors.lastname: Wan
authors.affiliation: State Key Laboratory of Virology & Key Laboratory of Analytical Chemistry for Biology and Medicine, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072, P.R. China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Collaborative Innovation Center of Chemistry for Life Sciences, School of Life Sciences, University of Sciences and Technology of China, Hefei, 230027, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
mesh_terms: D000081:Acetamides / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D001812:Blood-Brain Barrier / Q000378:metabolism; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D062105:Molecular Docking Simulation; D013329:Structure-Activity Relationship; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000081:Acetamides; D004791:Enzyme Inhibitors; C030686:acetamide; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases
keywords: cytotoxicity; inhibitors; molecular modeling; structure-activity relationships; virtual screening