The computational insights into the potential anti-cancer activity of natural drug INM-1 against HER2 and EGFR therapeutic targets

Inophyllamine-I (INM-1), a natural compound derived from <i>Callophyllum Inophyllum</i> plant source, has shown promising potential as an anticancer agent. Our earlier study on INM-1 proved its efficacy against non-small cell lung cancer (NSCLC) in mice. This study aimed to investigate the activity of INM-1 against two therapeutic targets human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR). Computational screening approaches, such as molecular docking and molecular dynamics simulations, were used to evaluate INM-1 binding affinity and stability with the active sites of HER2 and EGFR. The binding mechanism and binding energy of INM-1 inside the active sites of HER2 and EGFR were predicted using molecular docking. The docking studies revealed that INM-1 interacts well with critical amino acid residues in both targets' binding pockets. The binding energy estimations supported INM-1 predicted binding affinity for HER2 and EGFR. Over a time period of 200 ns, MD simulations revealed information about structural changes, flexibility, and intermolecular interactions. The stability of the HER2-INM-1 andEGFR_INM-1 complexes were revealed by the <i>G_MMPBSA</i> and Principal Component Analysis (PCA) for free energy landscape, which demonstrated persistent free energy of binding throughout the simulation. Overall, the results of the computational screening found that HER2 protein associated with INM-1 is more stable than the complex involving EGFR and INM-1. To confirm these results and investigate the effectiveness and safety of INM-1 as a targeted cancer therapy, additional experimental investigations are required.