title: Design novel inhibitors for treating cancer by targeting Cdc25B catalytic domain with de novo design.
abstract: The cell division cycle 25 (Cdc25) family of proteins is a group of highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent a group of attractive drug targets for anticancer therapies. To develop novel Cdc25B inhibitors, the ZINC database was screened for finding optimal fragments with de novo design approaches. As a result, top 11 compounds with higher binding affinities in flexible docking were obtained, which were derived from five novel scaffolds (scaffold C) consisting of the linker-part and two isolated scaffolds (scaffold A and B)located in the two binding domains (catalytic pocket and swimming pool), respectively. The subsequent molecular docking and molecular dynamics studies showed that these compounds not only adopt more favorable conformations but also have stronger binding interaction with receptor than the inhibitors identified previously. The additional absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions also indicted that the 11 compounds (especially Comp#1) hold a high potential to be novel lead compounds for anticarcinogen. Consequently, the findings reported here may at least provide a new strategy or useful insights for designing effective Cdc25B inhibitors.
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Wu
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Duan
authors.forename: Wei-Li
authors.initials: WL
authors.lastname: Dong
authors.forename: Xian-Chao
authors.initials: XC
authors.lastname: Cheng
authors.forename: Shu-Qing
authors.initials: SQ
authors.lastname: Wang
authors.affiliation: Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, 300070, P.R. China. wangshuqing@tijmu.edu.cn.
authors.forename: Run-Ling
authors.initials: RL
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D020134:Catalytic Domain / Q000187:drug effects*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases