NDLI: Probing the structural requirements of A-type Aurora kinase inhibitors using 3D-QSAR and molecular docking analysis

Content Provider	Springer Nature Link
Author	Zhang, Hui xiao Li, Yan Wang, Xia Wang, Yong hua
Copyright Year	2011
Abstract	Aurora-A, the most widely studied isoform of Aurora kinase overexpressed aberrantly in a wide variety of tumors, has been implicated in early mitotic entry, degradation of natural tumor suppressor p53 and centrosome maturation and separation; hence, potent inhibitors of Aurora-A may be therapeutically useful drugs in the treatment of various forms of cancer. Here, we report an in silico study on a group of 220 reported Aurora-A inhibitors with six different substructures. Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies were carried out using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques on this series of molecules. The resultant optimum 3D-QSAR models exhibited an r cv 2 value of 0.404-0.582 and their predictive ability was validated using an independent test set, ending in r pred 2 0.512-0.985. In addition, docking studies were employed to explore these protein–inhibitor interactions at the molecular level. The results of 3D-QSAR and docking analyses validated each other, and the key structural requirements affecting Aurora-A inhibitory activities, and the influential amino acids involved were identified. To the best of our knowledge, this is the first report on 3D-QSAR modeling of Aurora-A inhibitors, and the results can be used to accurately predict the binding affinity of related analogues and also facilitate the rational design of novel inhibitors with more potent biological activities. Figure A combined in silico modeling with 3D-QSAR and docking analysis was carried out on a total of 220 A-type Aurora kinase inhibitors. The results obtained from molecular docking and those from 3D-QSAR modeling can complement and validate each other very well.
Starting Page	1107
Ending Page	1122
Page Count	16
File Format	PDF
ISSN	16102940
Journal	Journal of Molecular Modeling
Volume Number	18
Issue Number	3
e-ISSN	09485023
Language	English
Publisher	Springer-Verlag
Publisher Date	2011-04-28
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Aurora-A Inhibitor 3D-QSAR CoMFA CoMSIA Molecular docking Computer Applications in Chemistry Molecular Medicine Health Informatics Biomedicine general Computer Application in Life Sciences Life Sciences
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Physical and Theoretical Chemistry Computational Theory and Mathematics Catalysis Inorganic Chemistry Computer Science Applications

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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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