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The epidermal growth factor receptor (EGFR) is a tyrosine kinase (TK) that belongs to the ErbB family and governs important cellular functions like reproduction, survival, motility, and differentiation. Overexpression, intensification, and alteration of EGFR occur in a wide range of human malignancies and are associated with tumor progression and decreased anticancer drug sensitivity. As a result, EGFR has been identified as one of the primary anticancer targets. As cancer is more likely to be poorly understood in traditional medical practices, the extrapolation of an ethnomedicine-led strategy to identifying and prioritizing anticancer medicinal plants has been questioned. Nonetheless, given the challenges of developing innovative anticancer drugs that are effective, safe, inexpensive, and widely available, ethnomedicinal studies play critical roles in identifying relevant medicinal plants that can be further investigated. This study employed pharmacophore modeling, molecular docking, and molecular dynamics simulation to develop an effective agent as an inhibitor for EGFR. The final findings revealed that the selected bioactive compound stabilized the EGFR protein. The optimum orientations of the various inhibitors was Friedelin and it was chosen and subjected, along with the FDA-approved drug, to molecular dynamics modeling to determine the molecular interaction of the medication with various mutational sites in order to deduce the suitable orientation for the inhibitors. The study also attest to the ethnomedicinal claims that ethnomedicinal plants played a huge role in anticancer drug discovery and that their exploration can change the bleak picture cancer paints in our societies today.

Background The difficulty in treating cancer resides in the ability to target abnormal proliferation while protecting normal proliferation, a feat that necessitates a thorough comprehension of both the normal and malignant mechanisms that promote cell growth and proliferation. Targeting cell death signaling pathways such as glycolytic and mitochondrial apoptosis is hallmark of many cancers the aim in which this research is ready to evaluate. Methods Atomistic molecular dynamics simulation of top hits after molecular docking and ADMET profiling of the ligands were performed for main protease-hit complexes. Results Docking scores of ligands used against PKM2 ranges from – 9.36 to – 12.1 kcal/mol, wherein, Mormordicoside-F2 had the highest score (-12.1kcal/mol) performing better than the FDA approved drug Benserazide(-7kcal/mol). Likewise, the scores ranged between – 8.51 and – 12.05kcal/mol for Anti-apoptotic Myeloid leukemia 1 (MCL-1), with Mormordicoside-F1 being the highest ranked compound performing better than the FDA approved drug Venetoclax(-8.6 kcal/mol). The RMSD plots obtained depicted stable trajectories with consistent and minor fluctuations implying that the protein (PKM2 and MCL1) backbone underwent minor structural perturbations. In addition, several significant peaks of increased fluctuations (RMSF) were also observed, indicating their increased interaction potential implying that the ligands could adapt effectively in the binding pocket of the protein. SASA analysis results shows that ligands used retained inside their shallow binding pocket. The phylogenetic tree obtained implies likelihood of reoccurring result of the Insilco profiling. Conclusion This research unveils that Mormordicoside F1 shows acceptable stability with Anti-apoptotic Myeloid leukemia 1 (MCL-1), likewise Mormordicoside F2 against PKM2. These hits may offer a more advantageous repurposing alternative.