Identification of Potential Lead Molecules against Dibenzo[a,l]pyrene-induced Mammary Cancer through Targeting Cytochrome P450 1A1, 1A2, and 1B1 Isozymes

Cytochrome P450 (CYP) isozymes are promising therapeutic targets against dibenzo[a,l]pyrene-induced mammary cancer. Current research aims to identify potential lead molecules against mammary cancer targetting CYP1A1, 1A2, and 1B1 using ligand-based virtual screening (LBVS), molecular interactions, MD simulation, and in vitro studies. The LBVS predicted 30,500 hits, which were reduced to 400 when sifted through Lipinski RO5, and ADMET parameters. These 400 compounds were carried forward for molecular docking with the selected CYP isozymes. The ligand CHEMBL224064 (CHEMBL1), CHEMBL2420083 (CHEMBL2), and CHEMBL61745 (CHEMBL3) depicted stronger binding respectively in CYP1A1 (-10-52 kcal/mol), 1A2 (-10.82 kcal/mol), and 1B1 (-10.78 kcal/mol) in comparison to known inhibitor alpha-naphthoflavone (ANF) (-9.13 kcal/mol, -9.66 kcal/mole, and -9.67 kcal/mol respectively in CYP1A1, 1A2, and 1B1). These compounds were found stable with their respective targets during MD studies of 50 ns duration. Furthermore, (3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide) (MTT) and enzyme inhibition assay elucidated and validated the inhibitory potential of identified ligands against mammary carcinomas. The study reveals a significant understanding of PAH-mediated mammary cancer and its prevention.