Computational discovery of natural product-based anti-cancer agents targeting antiapoptotic family proteins through bioinformatics approach

Cancer is a broader sense of illness, demonstrated by uncontrolled proliferation of cells, often associated with the overexpression of antiapoptotic proteins, which disrupts the normal apoptotic process, leading to an imbalance in tissue homeostasis. Aberrant apoptosis plays crucial roles, including enhancement of cell survival and proliferation, tumor progression and metastasis, drug resistance, and angiogenesis. Antiapoptotic proteins (Bcl-2 family) have become a promising target, due to their ability to regulate the apoptotic process. This study aimed to identify potential phytochemical inhibitors of the Bcl-2 family proteins using the bioinformatics approach. A total of 698 bioactive compounds of different medicinal plants were sourced from the online database. The virtual screening, followed by molecular docking and pharmacokinetics, was carried out to predict the binding interaction of each phytochemical to the targeted protein structures. Finally, the top-ranked protein-ligand with the most favorable binding energies was further assessed for a 200 ns molecular dynamic (MD) simulation study to investigate its binding stability and flexibility. Docking simulation revealed that Diosgenin showed the strongest binding affinities with Bcl-2 (−9 kcal/mol), Bcl-xL (−9.3 kcal/mol), Bcl-w (−8.5 kcal/mol), and Mcl-1 (−8.2 kcal/mol), respectively. This molecule exhibited stable performance over the simulation time compared with the control (Obatoclax), suggesting diosgenin as a potential inhibitor of Bcl-2 family proteins. The pharmacokinetic properties of this tested compound showed favorable and non-toxic profiles, which support it as a potential lead compound for further investigation. Therefore, these findings indicate that diosgenin may serve as a potential inhibitor of antiapoptotic proteins. However, further preclinical and clinical studies are required to validate its therapeutic efficacy and safety profile before clinical application.