Searching for BBB permeable phytochemical inhibitors for targeting brain cancer associated HER2 protein through free energy calculations and pharmacokinetic analysis

Among breast cancer subtypes, the HER2-positive phenotype is closely associated with brain metastases. While systemic treatments include monoclonal antibodies and synthetic drugs, their efficacy is often hindered by unfavourable pharmacodynamics, pharmacokinetic properties, and drug resistance. In this study, 17,870 phytochemicals, including experimentally validated phytochemicals for brain metastasis, sourced from the NPACT, a curated repository of plant-derived natural compounds with demonstrated anticancer activity, and IMPPAT, a curated database of all Indian medicinal phytochemicals, have been explored for lead identification against the HER2 target using molecular docking, molecular dynamics simulations, and MMPBSA-based free energy calculations. Veratramine (IMPHY006313) and Hydroxysanguinarine (IMPHY001305) were shown to have comparable or better binding affinity to FDA-approved HER2 inhibitors like Tucatinib. Additionally, Tanimoto similarity analysis revealed novel scaffolds in the lead phytochemicals when compared to FDA-approved drugs. Various pharmacokinetic properties like BBB permeability, P-gp substrate, CYP3A4 substrate, and other toxicity profiles have been used to filter out the best lead candidates. The insights from this study may significantly contribute to accelerating drug development efforts targeting HER2-positive brain cancer.