Abstract
In the proposed work, we have explicated the mechanism of dibenzo[a,l]pyrene (DBP) and benzo[a]pyrene (BP) modulated cell proliferation by assessing the plausible binding with CASPASES, BAX, Bcl-2, MDM2, p53, p21, p16, CylinD1-CDK4 complex, CylinE1-CDK2 complex, H-Ras, K-Ras, BRCA1, and BRCA2 through exploiting the inherent potential of AutoDock Tools 4.0. In silico findings revealed that potent carcinogenic metabolites of DBP (e.g., (-)-anti-DBPDE and (+)-syn-DBPDE) and BP (e.g., (+)-anti-BPDE) exhibited better binding interactions to Caspase-9 than Caspase-8 and Caspase-3. Feeble interactions of BAX and Bcl-2 with diol-epoxides of both PAHs were observed. Diol-epoxides of DBP and BP were found to bind to p53 with tighter interaction than MDM2 and p53-MDM2 complex. The p16 and Cyclin-CDK complexes were best docked to aforesaid metabolites as compared to p21. Moreover, stronger interactions of BRCA1 and BRCA2 with DBP and feeble interactions of BRCA1 and BRCA2 with BP were observed from docking results. Furthermore, stronger interactions of both DBP and BP with the H-Ras and K-Ras oncoproteins were found, while only DBP interacted relatively strongly with the BRCA1 and BRCA2, which were suggesting more carcinogenic nature of DBP than BP, a well-known observation in the wet lab. Besides giving structural insight into the mechanism of DBP and BP-mediated cell proliferation, these in silico findings may be helpful to understand the mechanistic nature of environmental carcinogens and their cellular targets.