Structural requirements of pyrimidine, thienopyridine and ureido thiophene carboxamide-based inhibitors of the checkpoint kinase 1: QSAR, docking, molecular dynamics analysis
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- 作者：Fangfang Wang (1)
Zhi Ma (1)
Yan Li (2)
Jinan Wang (1)
Yonghua Wang (13) yh_wang@nwsuaf.edu.cn - 关键词：Checkpoint kinase 1 – ; Molecular docking – ; Molecular dynamics – ; Quantitative structure activity relationship
- 刊名：Journal of Molecular Modeling
- 出版年：2012
- 出版时间：July 2012
- 年：2012
- 卷：18
- 期：7
- 页码：3227-3242
- 全文大小：1.4 MB
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- 刊物类别：Chemistry and Materials Science
- 刊物主题：Chemistry
Computer Applications in Chemistry
Biomedicine
Molecular Medicine
Health Informatics and Administration
Life Sciences
Computer Application in Life Sciences - 出版者：Springer Berlin / Heidelberg
- ISSN：0948-5023
文摘
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 (Ntraining = 51, Ntest = 16, Rcv2 = 0.47, Rpred2 = 0.7) for PP, (Ntraining = 45, Ntest = 9, Rcv2 = 0.52, Rpred2 = 0.75) for TP and (Ntraining = 58, Ntest = 15, Rcv2 = 0.67, Rpred2 = 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.