Targeting the cyclin-binding groove site to inhibit the catalytic activity of CDK2/cyclin A complex using p27KIP1-derived peptidomimetic inhibitors

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• 作者：Arumugasamy Karthiga (1)
  Sunil Kumar Tripathi (1)
  Ramasamy Shanmugam (2)
  Venkatesan Suryanarayanan (1)
  Sanjeev Kumar Singh (1)
  
  1. Computer Aided Drug Designing and Molecular Modeling Lab ; Department of Bioinformatics ; Alagappa University ; Karaikudi ; 630 003 ; Tamil Nadu ; India
  2. Department of Chemistry ; Thiagarajar College ; Madurai ; 625009 ; Tamil Nadu ; India
  
• 关键词：Protein鈥損rotein interaction ; Cyclin ; binding groove ; Peptidomimetic inhibitor ; Molecular docking ; MD simulation
• 刊名：Journal of Chemical Biology
• 出版年：2015
• 出版时间：January 2015
• 年：2015
• 卷：8
• 期：1
• 页码：11-24
• 全文大小：2,250 KB
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• 刊物主题：Physical Chemistry; Biophysics and Biological Physics; Cell Biology; Pharmacology/Toxicology; Biochemistry, general;
• 出版者：Springer Berlin Heidelberg
• ISSN：1864-6166

文摘

Functionally activated cyclin-dependent kinase 2 (CDK2)/cyclin A complex has been validated as an interesting therapeutic target to develop the efficient antineoplastic drug based on the cell cycle arrest. Cyclin A binds to CDK2 and activates the kinases as well as recruits the substrate and inhibitors using a hydrophobic cyclin-binding groove (CBG). Blocking the cyclin substrate recruitment on CBG is an alternative approach to override the specificity hurdle of the currently available ATP site targeting CDK2 inhibitors. Greater understanding of the interaction of CDK2/cyclin A complex with p27 (negative regulator) reveals that the Leu-Phe-Gly (LFG) motif region of p27 binds with the CBG site of cyclin A to arrest the malignant cell proliferation that induces apoptosis. In the present study, Replacement with Partial Ligand Alternatives through Computational Enrichment (REPLACE) drug design strategies have been applied to acquire LFG peptide-derived peptidomimetics library. The peptidomimetics function is equivalent with respect to substrate p27 protein fashion but does not act as an ATP antagonist. The combined approach of molecular docking, molecular dynamics (MD), and molecular electrostatic potential and ADME/T prediction were carried out to evaluate the peptidomimetics. Resultant interaction and electrostatic potential maps suggested that smaller substituent is desirable at the position of phenyl ring to interact with Trp217, Arg250, and Gln254 residues in the active site. The best docked poses were refined by the MD simulations which resulted in conformational changes. After equilibration, the structure of the peptidomimetic and receptor complex was stable. The results revealed that the various substrate protein-derived peptidomimetics could serve as perfect leads against CDK2 protein.