Covalent vs. Non‐Covalent Inhibition: Tackling Drug Resistance in EGFR – A Thorough Dynamic Perspective

Abstract

A persistent challenge in the treatment of non‐small cell lung cancer (NSCLC) with EGFR is the emergence of drug‐resistant caused by somatic mutations. The EGFR L858R/T790 M double mutant (EGFRDM) was found to be the most alarming variant. Despite the development of a wide range of inhibitors, none of them could inhibit EGFRDM effectively. Recently, 11h and 45a, have been found to be potent inhibitors against EGFRDM through two distinctive mechanisms, non‐covalent and covalent binding, respectively. However, the structural and dynamic implications of the two modes of inhibitions remain unexplored. Herein, two molecular dynamics simulation protocols, coupled with free‐energy calculations, were applied to gain insight into the atomistic nature of each binding mode. The comparative analysis confirmed that there is a significant difference in the binding free energy between 11h and 45a (ΔΔGbind=−21.17 kcal/mol). The main binding force that governs the binding of both inhibitors is vdW, with a higher contribution for 45a. Two residues ARG841 and THR854 were found to have curtailed role in the binding of 45a to EGFRDM by stabilizing its flexible alcohol chain. The 45a binding to EGFRDM induces structural rearrangement in the active site to allow easier accessibility of 45a to target residue CYS797. The findings of this work can substantially shed light on new strategies for developing novel classes of covalent and non‐covalent inhibitors with increased specificity and potency.

Lysine Covalent Antagonists of Melanoma Inhibitors of Apoptosis Protein

“…Recently, several covalent agents targeting surface Cys residues have entered clinical studies in oncology. ,− Based on this success and expanding on the relatively limited target space of the Cysteinome, we and others propose the introduction of suitable electrophiles to target other residues. ,,,, Our own recent studies ,, and others , suggested that it is possible to target Lys residues located at protein–protein interfaces, in principle expanding the target space of covalent antagonists to protein–protein interactions (PPIs) that have a Lys in the vicinity of their binding sites. , We recently found that certain substituted aryl-sulfonyl fluorides, namely, as in compounds 1 or 2 (Table ), possess a more balanced reactivity and stability in aqueous buffer and in cell, and hence, they can be used as electrophiles in pharmacological tools and perhaps future therapeutics . These previous studies were conducted targeting the BIR3 domains of XIAP, cIAP1, or cIAP2.…”

Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

“…Based on the type of inhibition of the EGFR kinase activity, the approved EGFR-TKIs can also be classified as reversible and irreversible inhibitors, as shown in Figure 5. For the first type, the inhibitors competitively bind to the ATP binding site in the EGFR through noncovalent interactions involving electrostatic, hydrogen-bonding, and hydrophobic interactions [24].…”

Piece of the Puzzle: Remdesivir disassemble the multimeric SARS-CoV-2 RNA-dependent RNA Polymerase Non-Structural Proteins (RdRp-NSPs) complex

“…The extent to which the compounds bind to the RdRp-NSP complex was determined using the MM/PBSA method. 37,38 Stable time-frames (170-200ns) were also selected to minimize entropical effects and our results are presented in Table 1. Accordingly, Rem-P 3 was strongly bound than ATP with ∆G bind difference of -13.2 kcal mol -1 .…”