In-Silico molecular docking analysis of monoclonal antibodies, approved inhibi-tors, and plant-based inhibitors targeting extracellular and intracellular HER2 receptor

Human epidermal growth factor receptor or HER2 is a key player in breast, ovarian, and gastric cancers. Mutations that cause HER2 overexpression may alter their binding properties and sensitivity towards certain drugs. This study investigates the sequential amino acid interactions of extracellular HER2 receptor with antibody and intracellular HER2 receptor with chemical inhibitor ligands using Molecular Docking to obtain the best drug model with the greatest binding affinity to HER2 receptor. Additionally, analysis of the HER2 protein-protein interactions, degradation mechanism, and ADMET profiling of the inhibitors was done. Molecular docking of extracellular HER2 receptor and antibodies trastuzumab and pertuzumab showed higher binding affinity for the improved trastuzumab. Molecular docking of intracellular HER2 receptor and 12 inhibitor ligands showed that plant-based inhibitor binding affinity was not higher than the control inhibitor, SYR127063. However, the opposite goes for the approved inhibitors tucatinib and lapatinib, as it gives a higher binding affinity than control. The best approved inhibitor and plant-based inhibitor according to the ADMET profile and molecular docking result were lapatinib and sanguinarine, respectively. The results had provided information on the binding properties of HER2 receptor with various inhibitors, which could be useful for future research on potential anti-cancer drugs to target and degrade HER2 receptor with optimal binding affinity. Furthermore, in vitro cell-based assays studies are required to test the efficacy of the plant-based inhibitors toward HER2 receptor and cellular safety.