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Noteworthy effect of slight variation in aliphatic chain length of trisubstituted imidazole inhibitors against epidermal growth factor receptor L858R/T790M/C797S mutant in cancer therapy
Author(s) -
Akher Farideh Badichi,
Farrokhzadeh Abdolkarim,
Soliman Mahmoud E. S.
Publication year - 2019
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13467
Subject(s) - t790m , chemistry , epidermal growth factor receptor , stereochemistry , hydrogen bond , potency , osimertinib , egfr inhibitors , receptor , in vitro , biochemistry , gefitinib , organic chemistry , molecule , erlotinib
11h is a very potent inhibitor against epidermal growth factor receptor triple mutation L858R/T790M/C797S ( EGFR TM ) with 13‐fold stronger potency than the FDA ‐approved osimertinib. Recently, two new EGFR TM inhibitors, 11d and 11e , were reported which revealed 2.8‐ and 2.3‐fold stronger potency than 11h , respectively. 11h , 11d, and 11e have the same structures but differ only in their aliphatic chain length. However, the exact effects of differential aliphatic chain length on the inhibitory potencies of these compounds require further elaboration at the atomistic level, hence the objective of this report. Various computational tools were employed for this purpose. From our findings, it was revealed that van der Waals (vdW) interactions modulate the binding mechanisms of these inhibitors and play the most important role in the differential inhibitory activities of 11d , 11h, and 11e . The strong hydrogen bond formation between the aliphatic chain of 11d and key residue ARG 841 was recognized as the reason for its higher activity and inhibitory potency relative to 11h and 11e . Moreover, the extension of the N‐terminal loop into the active site for vdW interaction with the phenyl group of 11e and carbon–hydrogen bond formed between the aliphatic chain of 11e and LEU 718 engendered a higher activity of 11e than 11h .