Molecular Insights into the Interaction of RONS and Thieno[3,2-c]pyran Analogs with SIRT6/COX-2: A Molecular Dynamics Study

Dharmendra K Yadav,Sandeep Chaudhary,Naresh Kumar,Surendra Kumar,Mi-Hyun Kim,Lalit Yadav,Hyung Sik Kim,Eun Ha Choi,Mahesh Teli,Sanjeev Misra,Saloni Saloni,Praveen Sharma

doi:10.1038/s41598-018-22972-9

Abstract

SIRT6 and COX-2 are oncogenes target that promote the expression of proinflammatory and pro-survival proteins through a signaling pathway, which leads to increased survival and proliferation of tumor cells. However, COX-2 also suppresses skin tumorigenesis and their relationship with SIRT6, making it an interesting target for the discovery of drugs with anti-inflammatory and anti-cancer properties. Herein, we studied the interaction of thieno[3,2-c]pyran analogs and RONS species with SIRT6 and COX-2 through the use of molecular docking and molecular dynamic simulations. Molecular docking studies revealed the importance of hydrophobic and hydrophilic amino acid residues for the stability. The molecular dynamics study examined conformational changes in the enzymes caused by the binding of the substrates and how those changes affected the stability of the protein-drug complex. The average RMSD values of the backbone atoms in compounds 6 and 10 were calculated from 1000 ps to 10000 ps and were found to be 0.13 nm for both compounds. Similarly, the radius of gyration values for compounds 6 and 10 were found to be 1.87 ± 0.03 nm and 1.86 ± 0.02 nm, respectively. The work presented here, will be of great help in lead identification and optimization for early drug discovery.

Highlights

IntroductionCOX enzyme activity is oxidative in nature and can lead to the production of reactive oxygen species (ROS) in activated inflammatory cells, which contributes to a pro-oxidant state[25]
COX-2 is involved in the pathogenesis of UV-induced non-melanoma skin cancers, and its inhibition is presumed to prevent the development of NMSCs
The connection of SIRT6 and COX-2 has been widely determined; an increase in SIRT-6 expression leads to a greater abundance of COX-2 while inhibition of SIRT-6 expression leads to a decrease in SIRT-6 expression

Summary

Introduction

COX enzyme activity is oxidative in nature and can lead to the production of reactive oxygen species (ROS) in activated inflammatory cells, which contributes to a pro-oxidant state[25]. All these lethal effects of chronic COX-2 up-regulation along with UV-induced p53 mutations combine to make a probable cause for the carcinogenic progression instigated and encouraged by chronic UV exposures. The RONS includes H2O2, NO2, N2O, NO3, N2O3, and N2O5 species and their excessive production aggravates diverse physiological states, including oxidative stress-induced inflammation, which leads to the apoptosis of cancer cells[31,32]. The relative stability and reactivity of designed thieno[3,2-c]pyran analogs and RONS were studied with the aid of unrestrained molecular dynamic simulation

Methods

Results

Conclusion