Inhibitory potentials of phytocompounds from Ocimum gratissimum against anti-apoptotic BCL-2 proteins associated with cancer: an integrated computational study

ABSTRACT The anti-apoptotic Bcl-2 family is intrinsically involved in regulating apoptosis. Over expression of these proteins is associated with cancer. Thus, inhibitors of these proteins will enhance the development of anti-apoptotic drugs. Herein, previously reported 103 Ocimum gratissimum derived phytochemicals were screened against five anti-apoptotic BCL-2 proteins (BCL-2, MCL-1, BCL-B BCL-XL and BFL-1) to identify potential inhibitors of multiple anti-apoptotic Bcl-2 proteins, using static and dynamic docking simulations, molecular dynamics (MD) simulations, clustering and Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) filtering analysis. Based on the minimal binding energy and a comparative reference inhibitors binding mode analysis, five lead phytochemicals (FLP) (ursolic acid, beta-sitosterol, luteolin, basilimoside and apigenin 7,4’,dimethyl ether) were identified. Ursolic acid, β-sitosterol and luteolin exhibited higher binding tendencies to the BH3 binding groove of multiple targets. Ursolic acid-Bcl-2 and luteolin-BCL-XL, complexes demonstrated structural stability in the simulated MD environment. Also, the FLP demonstrated favorable ADMET properties. Evidences from previously reported antiproliferative activities of ursolic acid, β-sitosterol and luteolin and results from this study suggest that the anti-proliferative activity of O. gratissimum may be as a result of the synergistic activities of, at least, the FLP. They are recommended for further study as natural-inhibitors against cancers defined by over expression of Bcl-2 family protein.