Enhancing therapeutic efficacy through Kaempferol and docetaxel combination: integrative binding and molecular dynamics study targeting Bcl-2 protein in breast cancer

Bcl-2 inhibits apoptosis by sequestering pro-apoptotic proteins, thereby preventing mitochondrial outer membrane permeabilization. Disruption of this interaction represents a promising strategy for restoring apoptosis signaling in cancer cells. This study investigated the binding affinity, conformational effects, and pharmacokinetic properties of docetaxel (DTX) and kaempferol (KAE) against Bcl-2. Blind molecular docking using AutoDock, molecular dynamics (MD) simulations, MM-PBSA binding energy calculations, and ADME drug-likeness analyses were conducted to characterize the interactions of DTX and KAE with Bcl-2. Molecular docking revealed favourable binding of DTX and KAE within the BH3-binding cleft of Bcl-2, with docking scores of −7.3 and − 7.7 kcal/mol, respectively. MM-PBSA analysis indicated stronger binding affinity for DTX (−28.90 ± 11.93 kcal/mol) than KAE (−23.63 ± 4.87 kcal/mol), with van der Waals interactions contributing predominantly to complex stabilization. Per-residue energy decomposition further revealed that binding of both compounds was primarily driven by hydrophobic interactions within the BH3-binding cleft. MD simulations conducted over 150 ns showed that DTX induced greater conformational fluctuations and correlated motions in Bcl-2, as evidenced by RMSD, RMSF, RoG, and DCCM analyses, suggesting reduced conformational stability. In contrast, KAE exhibited lower conformational fluctuations than the apo structure, suggesting stable binding within the BH3-binding cleft. ADME analysis predicted a more favourable pharmacokinetic property for KAE than DTX. In conclusion, these computational findings suggest that DTX may more strongly alter Bcl-2 conformational dynamics, whereas KAE exhibits favourable drug-like properties. The complementary dynamic and pharmacokinetic profiles of these compounds support further experimental evaluation as potential Bcl-2-modulating agents for cancer therapy.