Computer-aided identification of potential TYK2 inhibitors from drug database

Wei Zhang, Jianzong Li, Zhixin Huang, Haiyang Wang, Hao Luo, Xin Wang, Nan Zhou, Chuanfang Wu, Jinku Bao*

*Corresponding author for this work

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

TYK2 is a member of JAKs family protein tyrosine kinase activated in response to various cytokines. It plays a crucial role in transducing signals downstream of various cytokine receptors, which are involved in proinflammatory responses associated with immunological diseases. Thus, the study of selective TYK2 inhibitors is one of the most popular fields in anti-inflammation drug development. Herein, we adopted molecular docking, molecular dynamics simulation and MM-PBSA binding free energy calculation to screen potential TYK2-selective inhibitors from ZINC Drug Database. Finally, three small molecule drugs ZINC12503271 (Gemifloxacin), ZINC05844792 (Nebivolol) and ZINC00537805 (Glyburide) were selected as potential TYK2-selective inhibitors. Compared to known inhibitor 2,6-dichloro-N-{2-[(cyclopropylcarbonyl)amino]pyridin-4-yl}benzamide, these three candidates had better Grid score and Amber score from molecular docking and preferable results from binding free energy calculation as well. What's more, the ATP-binding site and A-loop motif had been identified to play key roles in TYK2-targeted inhibitor discovery. It is expected that our study will pave the way for the design of potent TYK2 inhibitors of new drugs to treat a wide variety of immunological diseases such as inflammatory diseases, multiple sclerosis, psoriasis inflammatory bowel disease (IBD) and so on.

Original languageEnglish
Pages (from-to)309-317
Number of pages9
JournalJournal of Molecular Structure
Volume1122
DOIs
Publication statusPublished - 15 Oct 2016
Externally publishedYes

Keywords

  • Kinase inhibitor
  • MD simulation
  • MM-PBSA
  • Molecular docking
  • TYK2

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