title: Three-dimensional quantitative structure-activity relationships of pyrrolopyridinone as cell division cycle kinase inhibitors by CoMFA and CoMSIA.
abstract: Seventy-five 1,5,6,7-tetrahydro-pyrrolo[3,2-C]pyridinone derivatives displaying potent activities against Cdc7 kinase were selected to establish 3D-QSAR models using CoMFA and CoMSIA methods. Internal and external cross-validation techniques were investigated as well as some measures including region focusing, progressive scrambling, bootstraping and leave-group-out. The satisfactory CoMFA model predicted a q (2) value of 0.836 and an r (2) value of 0.950, indicating that electrostatic and steric properties play a significant role in potency. The best CoMSIA model, based on a combination of steric, electrostatic and H-bond acceptor effects, predicted a q (2) value of 0.636 and an r (2) value of 0.907. The models were graphically interpreted using contour plots which provided insight into the structural requirements for increasing the activity of a compound. The final 3D-QSAR results could be used for rational design of potent inhibitors against Cdc7 kinase.
authors.affiliation: Faculty of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, People's Republic of China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Zheng
authors.forename: Gaokeng
authors.initials: G
authors.lastname: Xiao
authors.forename: Jialiang
authors.initials: J
authors.lastname: Guo
authors.forename: Longyi
authors.initials: L
authors.lastname: Rao
authors.forename: Wei
authors.initials: W
authors.lastname: Chao
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.forename: Pinghua
authors.initials: P
authors.lastname: Sun
mesh_terms: D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D003198:Computer Simulation; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship
chemical_list: D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D011728:Pyridones; C068619:CDC7 protein, human; D017346:Protein Serine-Threonine Kinases