Binding Pattern Elucidation of NNK and NNAL Cigarette Smoke Carcinogens with NER Pathway Enzymes: an Onco-Informatics Study

Abstract

Cigarette smoke derivatives like NNK (4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone) and NNAL(4-(methylnitrosamino)-1-(3-pyridyl)-1-butan-1-ol) are well-known carcinogens. We analyzed the interaction ofenzymes involved in the NER (nucleotide excision repair) pathway with ligands (NNK and NNAL). Binding wascharacterized for the enzymes sharing equivalent or better interaction as compared to +Ve control. The highestobtained docking energy between NNK and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.13 kcal/mol,-7.27 kcal/mol, -8.05 kcal/mol and -7.58 kcal/mol respectively. Similarly the highest obtained docking energybetween NNAL and enzymes RAD23A, CCNH, CDK7, and CETN2 were -7.46 kcal/mol, -7.94 kcal/mol, -7.83kcal/mol and -7.67 kcal/mol respectively. In order to find out the effect of NNK and NNAL on enzymes involvedin the NER pathway applying protein-protein interaction and protein-complex (i.e. enzymes docked with NNK/NNAL) interaction analysis. It was found that carcinogens are well capable to reduce the normal functioning ofgenes like RAD23A (HR23A), CCNH, CDK7 and CETN2. In silico analysis indicated loss of functions of thesegenes and their corresponding enzymes, which possibly might be a cause for alteration of DNA repair pathwaysleading to damage buildup and finally contributing to cancer formation.