Identification of small-molecule inhibitors targeting HER2 for breast cancer therapy using structure-based virtual screening, ADMET profiling, and molecular dynamics simulations.

Abstract

Human epidermal growth factor receptor 2 (HER2) is one of the key drivers of oncogenesis in HER2+ breast cancer. The overexpression resulted in uncontrollable cell division and additional tumor growth. Despite the current clinical therapeutics such as Tucatinib, Lapatinib, and Neratinib, the demand for novel inhibitors still exists. The research aimed to employ a multi-step computational framework for the discovery of highly effective small molecule inhibitors. The crystal structure of HER2 (PDB: 3PPO) was retrieved, and subsequently, virtual screening of small molecules was carried forward with the Mcule library. The screening resulted in filtering 100 compounds, out of which 45 were found to be non-toxic and had good ADME properties. BOILED-egg analysis predicted favorable HIA and BBB permeability properties surpassing the performance of clinically approved HER2 inhibitors. The docking studies singled out 11 compounds that had a high affinity towards the protein. On filtering those, the top two compounds achieved the best binding energies of -9.9 kcal/mol and -9.8 kcal/mol, respectively, outperforming the reference inhibitors. Moving ahead, 100 ns MD simulations confirmed enhanced stability, lower RMSF values, higher compactness, better solvation free energy, and persistent hydrogen bonding throughout the simulation period, showing the comparable results to the inhibitor. In comparison, findings reveal that Compound 1 hits structurally and energetically outperforming the existing therapeutics. Compound 2 showed a little less impact than compound 1, but can be considered as well as surpassing all the parameters successfully. Thereby, making the potential lead candidates for further experimental validation in breast cancer therapy.