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

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.