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Indexed by:期刊论文

Date of Publication:2012-07-01

Journal:JOURNAL OF MOLECULAR MODELING

Included Journals:SCIE、Scopus

Volume:18

Issue:7

Page Number:3227-3242

ISSN No.:1610-2940

Key Words:Checkpoint kinase 1; Molecular docking; Molecular dynamics; Quantitative structure activity relationship

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 (CHK1), 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 CHK1 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 CHK1.