Phytochemicals Daturilinol and Withametelin B identified as novel Bcl2 inhibitors via virtual screening and molecular simulations.

B-cell lymphoma 2 (Bcl-2) is a crucial regulatory protein involved in the control of apoptosis. Its overexpression in cancer cells facilitates evasion of programmed cell death, contributing to their survival and resistance to chemotherapy. Consequently, Bcl-2 has emerged as a promising drug target in cancer therapy. There is still ongoing research to find potential drug molecules that target Bcl-2 with higher potency, selectivity, and safety profile. This study was carried out by conducting a virtual screening of phytoconstituents from the IMPPAT database that could potentially inhibit the aberrant activity of Bcl-2. We first excluded compounds that did not abide by the Lipinski rule of five based on their physicochemical properties. We also calculated binding affinities, applied PAINS filters, and performed ADMET and PASS analyses, as well as interaction analyses, to identify compounds that were predicted to be safe and effective. Finally, two compounds, Daturilinol and Withametelin B, were selected because of their high binding and selective binding to Bcl-2. We analyzed these compounds in terms of time evolution by employing molecular dynamics simulation (MDS), principal component analysis (PCA), free energy landscape (FEL), and MM/PBSA. Consequently, we suggest that Daturilinol and Withametelin B could be further investigated in vitro and in vivo for therapeutic development against cancer.