Computational study of non-catalytic T-loop pocket on CDK proteins for drug development

doi:10.1088/1674-1056/26/12/128702

Abstract

Cyclin-dependent kinases (CDKs) are critical to the cell cycle and many other biological processes, and as such, are considered as one of the promising targets for therapy against cancer and other diseases. Most pan-CDK inhibitors bind to the highly conserved catalytic ATP-binding pocket and therefore lack the specificity to prevent side effects. It is desirable to develop drugs targeting non-catalytic pockets for specificity towards individual CDKs. Here we performed a systematic analysis of non-catalytic pockets on CDKs and identified a region underneath the T-loop, which we term TL pocket, for potential inhibitor development. Specifically, we compared the TL pockets of human CDK2 and CDK7-homolog Pfmrk of Plasmodium falciparum, a malaria-causing parasite. Molecular dynamics simulations of several short peptides revealed that this less conserved TL pocket could be used to design potentially specific inhibitors against malaria disease.

Keywords: cyclin-dependent kinases non-catalytic TL pocket inhibitor design

Received: 07 August 2017
Revised: 25 September 2017
Accepted manuscript online:

PACS:	87.14.E-	(Proteins)
	87.15.ap	(Molecular dynamics simulation)
	87.15.Qt	(Sequence analysis)
	87.19.X-	(Diseases)

Corresponding Authors: Chen Zeng, Chen Zeng
E-mail: chenz@gwu.edu;yjzhaowh@mail.ccnu.edu.cn

Cite this article:

Huiwen Wang(王慧雯), Kaili Wang(王凯丽), Zeyu Guan(管泽雨), Yiren Jian(简弋人), Ya Jia(贾亚), Fatah Kashanchi, Chen Zeng(曾辰), Yunjie Zhao(赵蕴杰) Computational study of non-catalytic T-loop pocket on CDK proteins for drug development 2017 Chin. Phys. B 26 128702

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Computational study of non-catalytic T-loop pocket on CDK proteins for drug development

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