Structural dynamics and kinase inhibitory activity of three generations of tyrosine kinase inhibitors against wild-type, L858R/T790M, and L858R/T790M/C797S forms of EGFR

Journal article

Authors/Editors

RUNGTIVA POO-ARPORN

Strategic Research Themes

Smart Healthcare (Strategic Research Themes)

Publication Details

Author list: Todsaporn, Duangjaia; Mahalapbutr, Panupong; Poo-arporn, Rungtiva P.; Choowongkomon, Kiattawee; Rungrotmongkol, Thanyada;

Publisher: Elsevier

Publication year: 2022

Volume number: 147

Start page: 105787

ISSN: 0010-4825

eISSN: 1879-0534

URL: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85133449449&doi=10.1016%2fj.compbiomed.2022.105787&partnerID=40&md5=9e5ffccf1d5b2ffc3a7c9a0b06d556b6

Languages: English-Great Britain (EN-GB)

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Abstract

Mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR), including L858R/T790M double and L858R/T790M/C797S triple mutations, are major causes of acquired resistance towards EGFR targeted drugs. In this work, a combination of comprehensive molecular modeling and in vitro kinase inhibition assay was used to unravel the mutational effects of EGFR on the susceptibility of three generations of EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib, dacomitinib, and osimertinib) in comparison with the wild-type EGFR. The binding affinity of all studied inhibitors towards the double and triple EGFR mutations was in good agreement with the experimental data, ranked in the order of osimertinib > afatinib > dacomitinib > erlotinib > gefitinib. Three hot-spot residues at the hinge region (M790, M793, and C797) were involved in the binding of osimertinib and afatinib, enhancing their inhibitory activity towards mutated EGFRs. Both double and triple EGFR mutations causing erlotinib and gefitinib resistance are mainly caused by the low number of H-bond occupations, the low number of surrounding atoms, and the high number of water molecules accessible to the enzyme active site. According to principal component analysis, the molecular complexation of osimertinib against the two mutated EGFRs was in a closed conformation, whereas that against wild-type EGFR was in an open conformation, resulting in drug resistance. This work paves the way for further design of the novel EGFR inhibitors to overcome drug resistance mechanisms. © 2022

Keywords

EGFR inhibitor, Kinase inhibition