Screening of Few Epoxides as mt-MAPK Inhibitor Preventing Granuloma Formation to Serve as Tubercular Antidote

Abhishek      Chowdhury; Paulomi      Paul; Pankaj      Chetia; Manabendra      Dutta Choudhury

Abstract

Tuberculosis is a major disease still today. Though instigation of Directly Observed Therapy, Short Course, (DOTS) has been widely implemented, new infection with tuberculosis in 2010-2011 was still recorded as 8.8 million. The synergy with multidrug resistant strains and HIV epidemics made the tuberculosis treatment difficult and necessitated the care discovery of new molecules and alternative drug targets.

Mycobacterium tuberculosis is known for its capacity of latent infection and also has a peculiar mechanism of granuloma formation where the pathogen multiplies. This process is mediated by various factors and mitogen activated protein kinase (mt-MAPK) is one of those. It works by suppressing the tumor necrosis factor (TNF-α). Computational screening of few epoxide derivatives for their anti-tubercular activities were performed followed by non-toxicity screening, docking in Flex-X and Autodock 4.2 and half maximal inhibitory concentration (IC50) prediction.

The docking score of one of the non-toxic derivative, (8S,9S,10S)-7,8,9,10-tetrahydrocyclopenta[ij]tetraphene-8,9,10-triol was found to be -26.07 and -6.02 Kcal/mol in Flex-X and Autodock 4.2 respectively and IC50 of 4.9x10-5 μM was found in quantitative structure activity relationship (QSAR) prediction.

The docking and QSAR result suggested (8S,9S,10S)-7,8,9,10-tetrahydrocyclopenta[ij]tetraphene-8,9,10-triol to be considered as mt-MAPK targeted granuloma formation inhibitor in tuberculosis treatment.

Keywords: (8S, 9S, 10S)-7, 8, 9, 10-tetrahydrocyclopenta[ij]tetraphene-8, 9, 10-triol, Mycobacterium tuberculosis, Mitogen Activated Protein Kinase, mt-MAPK, QSAR, Docking, DNA binding, dormant infection, tuberculosis, inflammatory responses, benzo(a)pyrene and aflatoxin, mt-MAPK