Molecular Dynamic Simulation Study of Newly Cytotoxic 2-(Aminomethyl)Benzimidazole Derivatives as Tyrosine Kinase Inhibitors

Receptor tyrosine kinases (RTK) are considered one of the main targets in cancer therapy due to their high expression. Unfortunately, multiple molecular mechanisms of resistance have been identified, leading to drug resistance and toxicity, which increases the need to discover new structural tyrosine kinase inhibitors. Instead of the rigid molecular docking method, molecular dynamic simulations can treat both the ligand and the protein in a flexible way. This lets the receptor-binding site fit around the new ligand. Also, the effect of explicit water molecules can be studied directly, and very accurate binding free energies can be obtained. The cytotoxic study does not explain the mechanism by which the tested compound could act, so further costly biological studies are needed. So, molecular dynamics is used as a computational technique that simulates the dynamic behavior of molecular systems as a function of time. Using Maestro v 13.0.135 interface (Schrodinger, New York, NY, 2021), molecular dynamic simulation was done with two proteins (EGFR and HER2) that are co-crystallized with the same ligand of a dual EGFR/HER2 inhibitor (TAK-285), and then they were tested with compounds of highly cytotoxic activity (2g and 4g) of suspected dual TKI activity from a previous study. According to the resulted data that were shown in the simulation interactions diagram reports, we recognize that the 2g compound showed a good interaction complex with both 3POZ (EGFR) and 3RCD (HRE2) proteins, while only the 4 g-3RCD complex showed a good interaction report. So, 2g could be considered a dual EGFR/HER2 inhibitor and 4g as an HER2 inhibitor, and for further investigation, both compounds could be tested further with other biological studies, especially enzyme inhibitory assays with suspected promising results.