title: Structure-based and shape-complemented pharmacophore modeling for the discovery of novel checkpoint kinase 1 inhibitors.
abstract: Checkpoint kinase 1 (Chk1), a member of the serine/threonine kinase family, is an attractive therapeutic target for anticancer combination therapy. A structure-based modeling approach complemented with shape components was pursued to develop a reliable pharmacophore model for ATP-competitive Chk1 inhibitors. Common chemical features of the pharmacophore model were derived by clustering multiple structure-based pharmacophore features from different Chk1-ligand complexes in comparable binding modes. The final model consisted of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), two hydrophobic (HY) features, several excluded volumes and shape constraints. In the validation study, this feature-shape query yielded an enrichment factor of 9.196 and performed fairly well at distinguishing active from inactive compounds, suggesting that the pharmacophore model can serve as a reliable tool for virtual screening to facilitate the discovery of novel Chk1 inhibitors. Besides, these pharmacophore features were assumed to be essential for Chk1 inhibitors, which might be useful for the identification of potential Chk1 inhibitors.
authors.affiliation: Laboratory of molecular design and drug discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
authors.forename: Xiu-Mei
authors.initials: XM
authors.lastname: Chen
authors.forename: Tao
authors.initials: T
authors.lastname: Lu
authors.forename: Shuai
authors.initials: S
authors.lastname: Lu
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Li
authors.forename: Hao-Liang
authors.initials: HL
authors.lastname: Yuan
authors.forename: Ting
authors.initials: T
authors.lastname: Ran
authors.forename: Hai-Chun
authors.initials: HC
authors.lastname: Liu
authors.forename: Ya-Dong
authors.initials: YD
authors.lastname: Chen
mesh_terms: D001570:Benzodiazepinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019311:Staurosporine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: C532363:3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide; D001570:Benzodiazepinones; D008024:Ligands; C532366:PF 00477736; D004364:Pharmaceutical Preparations; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D013876:Thiophenes; C054852:7-hydroxystaurosporine; D014508:Urea; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; D019311:Staurosporine