Structure-based and shape-complemented pharmacophore modeling for the discovery of novel checkpoint kinase 1 inhibitors.
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.
Chen
Xiu-Mei
XM
Laboratory of molecular design and drug discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, People's Republic of China.
Lu
Tao
T
Lu
Shuai
S
Li
Hui-Fang
HF
Yuan
Hao-Liang
HL
Ran
Ting
T
Liu
Hai-Chun
HC
Chen
Ya-Dong
YD
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
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