Computational Analysis using Multi-ligand Simultaneous Docking of Withaferin A and Garcinol Reveals Enhanced BCL-2 and AKT-1 Inhibition

Developing an effective medicine to combat cancer and elusive stem cells is crucial in the current scenario. Withaferin A and Garcinol, important phytoconstituents of Withania somnifera (Ashwagandha) and Garcinia indica (Kokum) respectively, known for their therapeutic efficiency, have been used for several decades for treating various disorders, because of their anti-cancerous, anti-inflammatory and anti-invasive properties. This study investigates the potentials of withaferin A and garcinol in inhibiting BCL-2 and AKT-1, crucial proteins contributing in cancer cell persistence by evading apoptosis, increased cell proliferation, and inflammation. Molecular docking techniques, including single docking and MLSD, were used to understand the binding interaction of the ligands with BCL-2 and AKT-1. MLSD highlighted inter-ligand interactions among withaferin A and garcinol, against BCL-2, with a binding affinity of -11.88 ± 0.12 kcal/mol, surpassing the binding affinity of venetoclax (-9.73 ± 0.1 kcal/mol) a commercial inhibitor of BCL-2. For AKT-1, the binding affinity of withaferin A and garcinol (-13.74 ± 0.08 kcal/mol) surpassed the binding affinity of melatonin (-7.24 ± 0.06 kcal/mol), a commercial inhibitor of AKT-1. The MLSD results highlight the combined effects of garcinol and withaferin A, highlighting the importance of considering both the interactions of the bioactive compounds in the development of new medicines and strategies targeting cancer and elusive stem cells.