Imidazole-[1,5- <i>a</i> ]-Pyridines Can Occupy the EGFR Allostery with a Strong Polar Interaction

The imidazole-[1,5-<i>a</i>]-pyridine derivatives were recently synthesized and showed remarkable bioactivity against three cancer cell lines, but an understanding of their activities is still missing. To prompt a detailed investigation into their molecular binding mechanisms, we carried out a comprehensive computational workflow for structure-based drug design. The protocol encompasses (i) ligand polarization using quantum chemical calculations, (ii) docking algorithms to generate initial protein-ligand conformations, (iii) molecular dynamics simulations to evaluate ligand diffusion within the protein pocket, and (iv) binding free energy calculations through the umbrella sampling molecular dynamics method. The inherent flexibility of the epidermal growth factor receptor (EGFR) kinase protein in an aqueous environment challenges the stability of ligand-protein associations. Of the 15 imidazole-pyridine compounds considered, after completing a total simulation time of 1.1 μs, only three compounds have been found to possess strong interactions with critical residues in the allosteric pocket of the EGFR inactive conformation in which the electrostatic potential energies play an important role. Notably, the compound named 3h389 carries out an exceptionally large binding free energy, outperforming the well-known allosteric inhibitor EAI045 considered a reference. More interestingly, the EGFR conformational changes under both 3h389 and EAI045 binding are similar. These results promote the imidazole-[1,5-<i>a</i>] compound denoted as 3h389 to be a highly strong candidate for a preclinical evaluation in cancer therapy. If such an evaluation can be performed, it underlines the utility of our computational pipeline for drug discovery efforts.