中国物理B ›› 2017, Vol. 26 ›› Issue (12): 128702-128702.doi: 10.1088/1674-1056/26/12/128702

所属专题： SPECIAL TOPIC — Soft matter and biological physics

• SPECIAL TOPIC—Soft matter and biological physics • 上一篇    下一篇

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

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)   

  1. 1. Institute of Biophysics and Department of Physics, Central China Normal University, Wuhan 430079, China;
    2. Department of Physics, The George Washington University, Washington, DC 20052, USA;
    3. George Mason University, Laboratory of Molecular Virology, Manassas, VA 20110, USA;
    4. QM Simulations Inc., 4464 Willow Rd, Pleasanton, CA 94588, USA
  • 收稿日期:2017-08-07 修回日期:2017-09-25 出版日期:2017-12-05 发布日期:2017-12-05
  • 通讯作者: Chen Zeng, Chen Zeng E-mail:chenz@gwu.edu;yjzhaowh@mail.ccnu.edu.cn

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

Huiwen Wang(王慧雯)1, Kaili Wang(王凯丽)1, Zeyu Guan(管泽雨)1, Yiren Jian(简弋人)2,4, Ya Jia(贾亚)1, Fatah Kashanchi3, Chen Zeng(曾辰)1,2, Yunjie Zhao(赵蕴杰)1   

  1. 1. Institute of Biophysics and Department of Physics, Central China Normal University, Wuhan 430079, China;
    2. Department of Physics, The George Washington University, Washington, DC 20052, USA;
    3. George Mason University, Laboratory of Molecular Virology, Manassas, VA 20110, USA;
    4. QM Simulations Inc., 4464 Willow Rd, Pleasanton, CA 94588, USA
  • Received:2017-08-07 Revised:2017-09-25 Online:2017-12-05 Published:2017-12-05
  • Contact: Chen Zeng, Chen Zeng E-mail:chenz@gwu.edu;yjzhaowh@mail.ccnu.edu.cn

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摘要：

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.

关键词: cyclin-dependent kinases, non-catalytic, TL pocket, inhibitor design

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.

Key words: cyclin-dependent kinases, non-catalytic, TL pocket, inhibitor design

中图分类号:  (Proteins)

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