Inhibition of striatal-enriched protein tyrosine phosphatase by targeting computationally revealed cryptic pockets

Xuben Hou, Jin peng Sun, Lin Ge, Xiao Liang, Kangshuai Li, Yingkai Zhang, Hao Fang

Research output: Contribution to journalArticle

Abstract

Cryptic pockets, which are not apparent in crystallographic structures, provide promising alternatives to traditional binding sites for drug development. However, identifying cryptic pockets is extremely challenging and the therapeutic potential of cryptic pockets remains unclear. Here, we reported the discovery of novel inhibitors for striatal-enriched protein tyrosine phosphatase (STEP), a potential drug target for multiple neuropsychiatric disorders, based on cryptic pocket detection. By combining the use of molecular dynamics simulations and fragment-centric topographical mapping, we identified transiently open cryptic pockets and identified 12 new STEP inhibition scaffolds through structure-based virtual screening. Site-directed mutagenesis verified the binding of ST3 with the predicted cryptic pockets. Moreover, the most potent and selective inhibitors could modulate the phosphorylation of both ERK1/2 and Pyk2 in PC12 cells.

Original languageEnglish (US)
Article number112131
JournalEuropean journal of medicinal chemistry
Volume190
DOIs
StatePublished - Mar 15 2020

Keywords

  • Cryptic pocket
  • Inhibitor
  • Striatal-enriched protein tyrosine phosphatase
  • Virtual screening

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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