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

Abstract

11h is a very potent inhibitor against epidermal growth factor receptor triple mutation L858R/T790M/C797S (EGFRTM) with 13‐fold stronger potency than the FDA‐approved osimertinib. Recently, two new EGFRTM 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 ARG841 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 LEU718 engendered a higher activity of 11e than 11h.

Impact of HEC72702 chirality on the selective inhibition of hepatitis B virus capsid dimer: A dynamics–structure–energetics perspective

“…This helps identify crucial binding site residues and their interaction patterns which would facilitate further structure‐based drug design efforts. Herein, the MM/GBSA method was used to estimate the differential binding affinities of ( R,R ) ‐ and ( R,S ) ‐7 diastereomers toward HBVC dimer (HBVCd) (Akher, Farrokhzadeh, Olotu, Agoni, & Soliman, 2019b; Akher, Farrokhzadeh, Ravenscroft, & Kuttel, 2019c; Akher, Farrokhzadeh, & Soliman, 2019a; Farrokhzadeh, Akher, Olotu, Soliman, & Van Heerden, 2019b; Farrokhzadeh, Akher, & Soliman, 2019a; Genheden & Ryde, 2012). This enabled the determination of the binding energy profiles that included other components such as electrostatic and van der Waals energies.…”

A Mechanistic Study of a Potent and Selective Epidermal Growth Factor Receptor Inhibitor against the L858R/T790M Resistance Mutation

“…In this study, an in-house cMD simulation protocol was employed that has been validated as previously reported. ,− The Amber14-integrated particle mesh Ewald molecular dynamics (PMEMD) graphical processing unit (GPU) was used to perform the cMD simulations wherein the generalized AMBER force field “leap.gaff” was used to model the inhibitor ( 20g ), and the “leaprc.ff14SB” force field, the protein biomolecules. Moreover, the covalently linked 20g -Cys797 was parametrized using the integrated Antechamber module, and the Link, Edit, and Parm (LEaP) module was used to create a library for the covalent binder.…”

How Different Substitution Positions of F, Cl Atoms in Benzene Ring of 5-Methylpyrimidine Pyridine Derivatives Affect the Inhibition Ability of EGFRL858R/T790M/C797S Inhibitors: A Molecular Dynamics Simulation Study

“…All six inhibitors belong to reversible inhibitors which are located in the cavity of the hydrophobic environment, and the location of these competitive inhibitors is the reported ATP binding site [38][39][40][41][42][43], which is involved van der Waals interactions and electrostatic interactions. It is observed that there are nearly 20 amino acids in 3.5 Å around the inhibitors from Figure S1, which are hydrophobic amino acids-Leu718, Gly719, Val726, Ala743, Met766, Leu777, Leu788, Met790, Leu792, Met793, Pro794, Phe795, Gly796, Leu844-and hydrophilic amino acids-Lys745, Cys775, Gln791, Ser797; it can be seen that the inhibitors are bounded to a large hydrophobic cavity, which is defined as "mouth" and is the same as below.…”