Molecular interaction analysis of cigarette smoke carcinogens NNK and NNAL with enzymes involved in DNA repair pathways: An in silico approach.

Qazi Mohd Sajid Jamal,Mohd Haris Siddiqui,Mohtashim Lohani,Gulshan Wadhwa,Shailendra Kumar Gupta,Mohd Haneef

doi:10.6026/97320630008795

Abstract

DNA damage occurs almost all the times in cells, but is repaired also continuously. Occurrence of all these mutations and their accumulation in one cell which finally becomes tumorigenic/carcinogenic appears possible if the DNA repair mechanism is hampered. We hypothesize that alterations in DNA repair pathways, either all or at least at one i.e. genetic, translational or posttranslational level, becomes quite imperative for the initiation and progression of Cancer. Therefore, we investigated the interaction capability of some carcinogens with the enzymes involved in the DNA repair mechanisms. Cigarette smoke's derivatives like NNK and NNAL are well established carcinogens. Hence, we analyzed 72 enzymes involved in the DNA repair Mechanisms for their interactions with ligands (NNK and NNAL). The binding efficiencies with enzymes ranging from +36.96 to -7.47 Kcal/Mol. Crystal Structure of Human Carbonmonoxy-Haemoglobin at 1.25 Å Resolution, PDB ID-1IRD as a +Ve control, showed binding energy -6.31 to -6.68 Kcal/Mol. and Human heat shock factor-binding protein 1, PDB ID- 3CI9 as a -Ve control, showed - 3.91 to +2.09 Kcal/Mol. Binding was characterized for the enzymes sharing equivalent or better interaction as compared to +Ve control. Study indicated the loss of functions of these enzymes, which probably could be a reason for fettering of DNA repair pathways resulting in damage accumulation and finally cancer formation.

Highlights

DNA damage occurs almost all the times in cells, but is repaired continuously
The 1IRD (Crystal Structure of Human CarbonmonoxyHaemoglobin at 1.25 Å Resolution) was employed as a positive control and 3CI9 (Human heat shock factor-binding protein 1) as a negative control to validate our docking analysis. Docking results of these proteins showed that 1IRD docked with NNK, observed binding energy was -6.68 Kcal/Mol, it docked with NNAL and observed binding energy was -6.31 Kcal/Mol. 3CI9 docked with NNK with observed binding energy of -3.91 Kcal/Mol, it docked with NNAL with binding energy of +2.09 Kcal/Mol
After analysing the binding energy of distinct formed clusters, top 4 enzymes those shown the higher efficiency to bind with ligands

Summary

Introduction

DNA damage occurs almost all the times in cells, but is repaired continuously. For a cell to become transformed accumulation of all the damage/mutations in cell is mandatory and which appears, to be possible only if mutation escape the repair mechanism, in other words, the repair pathways are hampered. Studies have shown that DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 1,000 to 1,000,000 molecular lesions per cell per day While this constitutes only 0.000165% of the human genome's approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cell’s ability to carry out its function and appreciably increase the likelihood of cancer formation [1]. Occurrence of all these mutations and their accumulation in one cell which becomes tumorigenic/carcinogenic appears. Presence of substantial amount of NNK in tobacco products plays a significant role as a cause of cancer in population using these products [4]

Methods

Findings

Discussion

Conclusion