GC–MS–Identified Phytochemicals from Dimocarpus longan Leaves as Promising HER2 Inhibitors for Breast Cancer: Molecular Docking, ADMET, and Toxicity Assessment

Breast cancer is still a leading cause of cancer-related deaths globally, and human epidermal growth factor receptor 2 (HER2) overexpression is known to be associated with aggressive tumor characteristics and drug resistance. Although the development of clinically used HER2 inhibitors has shown improved outcomes for patients, their efficacy is often hampered by factors such as low bioavailability, drug resistance, and toxicity. In this research, the leaves of Dimocarpus longan were investigated as a natural source of new lead compounds for the development of next-generation HER2 inhibitors. Phytochemicals isolated from methanolic extracts of the leaves were assessed using an integrated computational approach that included molecular docking, pharmacokinetic analysis, toxicity prediction, and structure-activity relationship analysis. Some phytocompounds showed positive binding affinity interactions with the HER2 kinase domain, displaying affinity interaction profiles similar to known HER2 kinase inhibitors, including essential hydrogen bonding and hydrophobic interactions in the active site. In silico pharmacokinetic analysis showed that many compounds had desirable drug-likeness properties, including good gastrointestinal absorption and conformance to essential medicinal chemistry guidelines. Moreover, toxicity profiling indicated lower probabilities of hepatic, neurological, and immunological toxicities for some candidates. Structure-activity relationship analysis emphasized the significance of harmonious polar functional groups and hydrophobic cores in potentiating HER2 kinase inhibition. In conclusion, the results suggest that D. longan-derived phytocompounds are promising candidates for the development of safer and more bioavailable HER2-targeting drugs. Further experimental verification and rational optimization are required to translate these candidates into potential therapeutic agents for HER2-positive breast cancer.