Integrated phytochemical and computational approaches to identify candidate Bcl-2 inhibitors from Caesalpinia mimosoides: Toward translational anticancer strategies.

Caesalpinia mimosoides has long been used in traditional Indian healing practices to address a range of health concerns. However, its potential for use as an anticancer agent has not been fully explored. The study aimed to perform a detailed phytochemical analysis of root extracts from C. mimosoides and to evaluate their anticancer potential against the anti-apoptotic Bcl-2 protein using computational methods. UPLC-MS/MS analysis of root extracts from C. mimosoides, prepared using hexane, ethyl acetate, methanol, and water, identified notable bioactive compounds. Molecular docking was used to assess binding modes, binding affinity (ΔG), ligand efficiency, inhibition constants (Ki), and the spectrum of non-covalent intermolecular interactions between Bcl-2 and the identified phytoconstituents. Molecular docking studies, along with Molecular dynamics simulations, were performed and further analyses with respect to binding of the phytochemicals, specifically targeting the Bcl-2 hydrophobic BH3-binding groove, were performed, using AutoDock Vina, with grid parameters defined through PyRx, and the Gromacs 2021.4 software for Molecular Dynamics Simulation studies. Pharmacokinetic profiling demonstrated that the prioritized compounds exhibited favourable ADMET characteristics, drug-likeness, and the potential to modulate the mitochondrial-mediated apoptotic pathway through targeted Bcl-2 inhibition, supporting their role as promising plant-derived alternatives to synthetic Bcl-2 inhibitor venetoclax (ABT-199). Key bioactive compounds identified were nodakenin (CID: 73191), leosibiricin (CID: 101944737), and 2-benzylidenesuccinic acid (CID: 820630), with binding affinities ranging from -5.4 to -9.8 kcal/mol, indicating a promising interaction strength with the Bcl-2 protein. The Nodakenin molecule consistently exhibited the most favourable structural stability profile in MD simulations, underscoring its potential as a promising inhibitor of the anti-apoptotic Bcl-2 protein for anticancer therapeutics. Besides, the MM/PBSA-based binding free energy analysis shows that Venetoclax exhibits the most favourable binding (-78.84 ± 4.73 kcal/mol), followed by Nodakenin (-15.54 ± 3.76 kcal/mol), which also displays a favourable binding profile. This study demonstrates the anticancer potential of C. mimosoides through comprehensive phytochemical profiling and molecular docking, providing strong evidence for its role as a promising source of plant-derived Bcl-2 inhibitors for targeted cancer therapy.