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Molecular modeling provides a structural basis for PERK inhibitor selectivity towards RIPK1

Journal article
Authors C. Chintha
Antonio Carlesso
A. M. Gorman
A. Samali
Leif A Eriksson
Published in RSC Advances
Volume 10
Issue 1
Pages 367-375
Publication year 2020
Published at Department of Chemistry and Molecular Biology
Pages 367-375
Language en
Links dx.doi.org/10.1039/c9ra08047c
Keywords high-throughput docking, kinase inhibitors, protein, binding, discovery, potent, gsk2606414, prediction, Chemistry
Subject categories Biochemistry and Molecular Biology

Abstract

Protein kinases are crucial drug targets in cancer therapy. Kinase inhibitors are promiscuous in nature due to the highly conserved nature of the kinase ATP binding pockets. PERK has emerged as a potential therapeutic target in cancer. However, PERK inhibitors GSK2606414 and GSK2656157 also target RIPK1 whereas AMG44 is more specific to PERK. To understand the structural basis for the selectivity of PERK ligands to RIPK1 we have undertaken a detailed in silico analysis using molecular docking followed by molecular dynamics simulations to explore the selectivity profiles of the compounds. Although the binding sites of PERK and RIPK1 are similar, their binding response to small molecules is different. The docking models revealed a common binding mode for GSK2606414 and GSK2656157 in the RIPK1 binding site, similar to its cognate ligand. In contrast, AMG44 had a strikingly different predicted binding profile in the RIPK1 binding site with both rigid docking and induced fit docking settings. Our study shows a molecular mechanism responsible for dual targeting by the GSK ligands. More broadly, this work illustrates the potential of molecular docking to correctly predict the binding towards different kinase structures, and will aid in the design of selective PERK kinase inhibitors.

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