Computational and pharmacophore-based study of Camellia sinensis phytochemicals targeting BRAF in melanoma.

Melanoma is the deadliest kind and most invasive form of skin cancer caused by exposure to UV light and mutation in BRAF signaling protein. Plant-derived phytochemicals have several anticancer properties and used as therapeutic option since ancient era. The purpose of this research is to look at their potential for BRAF protein inhibition in melanoma through molecular docking, pharmacophore modeling, pharmacokinetics, molecular dynamic stimulation and quantum mechanics studies using the phytochemicals from green tea (Camellia sinensis). Drug discovery research was done through in series of computational approach, where protein BRAF (PDB ID: 4MNF) preparation, compounds retrieval and pharmacology properties analysis were done. To verify the stability and affinity of protein–ligand binding, post-docking, pharmacophore modelling, and dynamics stimulation were carried out in the virtual screening programs including AutoDock Vina, MOE, SwisDock and Schrodinger. During the molecular docking experiment of 248 phytochemicals of tea, theaflagallin exhibited a greater binding potential (− 10.8 kcal/mol) compared to the control drug plixorafenib (− 11 kcal/mol) and other top two compounds epigallocatechin 3-O-cinnamate (− 10.3 kcal/mol), and epicatechin gallate (− 9.8 kcal/mol). Post-docking validation confirmed robust ligand binding with accurate pose predictions, while structure-based pharmacophore modeling of BRAF identified key hydrogen-bonding, aromatic, and hydrophobic features essential for effective inhibition by the studied phytochemicals. The chosen phytochemicals are found to be non-toxic, anti-carcinogenic, anti-mutagenic, anti-neoplastic, TP53 expression enhancer, hepatoprotectant, cardioprotectant and possess drug-like properties based on the pharmacological and biological activity studies. In addition, molecular dynamics simulations over 200 ns demonstrated stable binding of all ligands to BRAF, with theaflagallin exhibiting the highest structural stability and strongest interactions, surpassing the control drug Plixorafenib in compactness, polar surface exposure, and binding consistency. The MM-GBSA free energies for these compounds were − 66.55 kcal/mol, − 74.40 kcal/mol, and − 100.57 kcal/mol respectively. The energy gaps between the HOMO and LUMO provided insight into the reactivity of these compounds. Considering the present results, the reported three phytochemicals studied in this study may be used as potential drugs to cure melanoma in near future after executing in-vitro and in-vivo studies.