Discovery of novel TrkA allosteric inhibitors: Structure-based virtual screening, biological evaluation and preliminary SAR studies

Eur J Med Chem. 2022 Jan 15:228:114022. doi: 10.1016/j.ejmech.2021.114022. Epub 2021 Nov 30.

Abstract

Tropomyosin receptor kinases A (TrkA) is a potential therapeutic target for the treatment of numerous tumor types and chronic pain. However, most of the reported TrkA inhibitors are ATP competitive pan-Trks inhibitors that lack subtype selectivity. A selective TrkA inhibitor may provide valuable therapeutic benefits. Here, we described the discovery of novel TrkA allosteric inhibitors by structure-based virtual screening. A promising hit (D5261, TrkA cell IC50 = 3.32 μM) was selected for further studies. The binding free energy between TrkA and D5261 was calculated. In addition, the preliminary structure-activity relationship (SAR) studies with D5261 were investigated. The results suggest that D5261 can be used as a starting point for development of TrkA allosteric inhibitors.

Keywords: Allosteric inhibitor; Molecular dynamics simulation; Tropomyosin-receptor kinase A; Virtual screening.

MeSH terms

  • Allosteric Regulation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Drug Evaluation, Preclinical
  • Humans
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Receptor, trkA / antagonists & inhibitors*
  • Receptor, trkA / metabolism
  • Structure-Activity Relationship

Substances

  • NTRK1 protein, human
  • Protein Kinase Inhibitors
  • Receptor, trkA