title: Structural requirements of pyrimidine, thienopyridine and ureido thiophene carboxamide-based inhibitors of the checkpoint kinase 1: QSAR, docking, molecular dynamics analysis.
abstract: Our focus of current research is directed toward clarification of novel inhibitors (pyrazolo[1,5-a] pyrimidine (PP), thienopyridines (TP) and 2-ureido thiophene carboxamide (UTC) derivatives) targeting Checkpoint kinase 1 (CHK(1)), which is an oncology target of significant current interest. Our computational approaches include: (i) QSAR analysis was carried out on the computed steric/electrostatic/hydrophobic/hydrogen bond donor/hydrogen bond acceptor interactions with the pseudoreceptor surface, which yielded predictive models capable of explaining much of the variance of inhibitors. The resultant optimum QSAR/CoMFA models exhibited (N(training) = 51, N(test) = 16, R(cv) (2) = 0.47, R(pred) (2) = 0.7) for PP, (N(training) = 45, N(test) = 9, R(cv) (2) = 0.52, R(pred) (2) = 0.75) for TP and (N(training) = 58, N(test) = 15, R(cv) (2) = 0.67, R(pred) (2) = 0.88) for UTC. (ii) Molecular docking and molecular dynamics simulations experiments of the inhibitors into the binding site of CHK(1) aided the interpretation of the QSAR models and demonstrated the binding modes in the aspects of inhibitor's conformation, subsite interaction, and hydrogen bonding interactions, which indicated that a set of critical residues (Cys87, Glu91, Glu85, Ser147, Asp148, Glu17, Leu84 and Asn135) played a key role in the drug-target interactions. The obtained results in the present work will be fruitful for the design of new potent and selective inhibitors of CHK(1).
authors.affiliation: Bioinformatics Center, Northwest A&F University, Yangling, Shaanxi 712100, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Wang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Ma
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Jinan
authors.initials: J
authors.lastname: Wang
authors.forename: Yonghua
authors.initials: Y
authors.lastname: Wang
mesh_terms: D001665:Binding Sites; D000071877:Checkpoint Kinase 1; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D013876:Thiophenes / Q000737:chemistry*
chemical_list: D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D013876:Thiophenes; C446540:thienopyridine; D011494:Protein Kinases; D000071877:Checkpoint Kinase 1; C030986:pyrimidine