Molecular docking and molecular dynamics simulations reveal the clinical resistance of the gatekeeper mutation V564F of FGFR2 against Infigratinib

Autor: Guodong Zheng, Wuxia Liu, Qian Zhang, Tuo Shen, Jingfeng Zhang, Lei Jiang, Wenqi Liang, Bin Zhou, Ling Liu, Shenqian Xu, Minyu Li
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: Journal of Experimental Nanoscience, Vol 18, Iss 1 (2023)
Druh dokumentu: article
ISSN: 17458080
1745-8099
1745-8080
DOI: 10.1080/17458080.2023.2264521
Popis: Fibroblast growth factor receptor 2 (FGFR2), as a transmembrane receptor tyrosine kinase, is implicated in a plethora of human cancers, including intrahepatic cholangiocarcinomas, breast cancers, and non-small cell lung cancer. The clinically relevant V564F gatekeeper mutation conferred resistance to current FGFR2 drug − Infigratinib. In this study, the protein − ligand interactions between FGFR2 kinase domain (wild-type and V564F) and Infigratinib were compared through an integrated computational method. The multiple, large-scale molecular dynamics (MD) simulations, together with dynamic cross-correlation analysis and binding free energy calculations suggested that the resistant mutation may not trigger the conformational changes of the FGFR2 kinase domain. The simulation results also indicated that the driving force to decrease the binding affinity of Infigratinib to the FGFR2 V564F variant derived from the difference in the protein − ligand hydrogen bonding interactions. Moreover, the per-residue free energy decomposition analysis revealed that the reduced contributions from several residues in the ATP-binding site of FGFR2, especially Glu565 and Ala567 located at the kinase hinge domain, were the key residues responsible for the loss of binding affinity of Infigratinib to the V564F variant. This study may offer useful information for the design of novel selective kinase inhibitors targeting FGFR2.
Databáze: Directory of Open Access Journals
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