In Silico Design, Extended Molecular Dynamic Simulations and Binding Energy Calculations for a New Series of Dually Acting Inhibitors against EGFR and HER2

TL;DR

This study uses extended molecular dynamics simulations and binding energy calculations to analyze and design dual inhibitors targeting EGFR and HER2, providing insights into their binding mechanisms and potential effectiveness against mutant strains.

Contribution

It introduces a new in silico approach combining extended simulations and scoring techniques to design and evaluate dual inhibitors for EGFR and HER2, including mutant strains.

Findings

Certain substitution patterns enhance binding to conserved water molecules.

New inhibitors form stable interactions with mutant EGFR strains.

Comparison reveals differences in binding mechanisms among inhibitors.

Abstract

Starting from the lead structure we have identified in our previous works, we are extending our insight understanding of its potential inhibitory effect against both EGFR and HER2 receptors. Herein and using extended molecular dynamic simulations and different scoring techniques, we are providing plausible explanations for the observed inhibitory effect. Also, we are comparing the binding mechanism in addition to the dynamics of binding with two other approved inhibitors against EGFR (Lapatinib) and HER2 (SYR). Based on this information, we are also designing and in silico screening new potential inhibitors sharing the same scaffold of the lead structure. We have chosen the best scoring inhibitor for additional in silico investigation against both the wild-type and T790M mutant strain of EGFR. It seems that certain substitution pattern guarantees the binding to the conserved water molecule commonly observed with kinase crystal structures. Also, the new inhibitors seem to form a stable interaction with the mutant strain as a direct consequence of their enhanced ability to form additional interactions with binding site residues.