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

Jing Guo; Shuang Xiang; Jie Wang; Yang Zhou; Zuqin Wang; Zhang Zhang; Ke Ding; Xiaoyun Lu

doi:10.1016/j.ejmech.2021.114022

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.

Authors

Jing Guo¹, Shuang Xiang¹, Jie Wang¹, Yang Zhou¹, Zuqin Wang¹, Zhang Zhang¹, Ke Ding¹, Xiaoyun Lu²

Affiliations

¹ International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China.
² International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, 510632, China. Electronic address: luxy2016@jnu.edu.cn.

PMID: 34871843
DOI: 10.1016/j.ejmech.2021.114022

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