Abstract
Simple SummaryIn an era where the world faces new diseases and pathogens, another emerging challenge is neglected pathogens becoming more notorious. Transcriptional regulators play a vital role in the pathogenesis and survival of these pathogens. Hence, characterizing transcriptional regulators, either in vitro or in silico, is of great importance. Here, we present the first structural characterization of a GntR/HutC regulator in Mycobacterium tuberculosis via in silico methods. We have suggested its possible role and potential as a drug target as well as identified possible drug leads that can be used for further improvements.Mycobacterium tuberculosis is a well-known pathogen due to the emergence of drug resistance associated with it, where transcriptional regulators play a key role in infection, colonization and persistence. The genome of M. tuberculosis encodes many transcriptional regulators, and here we report an in-depth in silico characterization of a GntR regulator: MoyR, a possible monooxygenase regulator. Homology modelling provided a reliable structure for MoyR, showing homology with a HutC regulator DasR from Streptomyces coelicolor. In silico physicochemical analysis revealed that MoyR is a cytoplasmic protein with higher thermal stability and higher pI. Four highly probable binding pockets were determined in MoyR and the druggability was higher in the orthosteric binding site consisting of three conserved critical residues: TYR179, ARG223 and GLU234. Two highly conserved leucine residues were identified in the effector-binding region of MoyR and other HutC homologues, suggesting that these two residues can be crucial for structure stability and oligomerization. Virtual screening of drug leads resulted in four drug-like compounds with greater affinity to MoyR with potential inhibitory effects for MoyR. Our findings support that this regulator protein can be valuable as a therapeutic target that can be used for developing drug leads.
Highlights
Tuberculosis (TB), a disease that has plagued humankind throughout history, is caused mainly by the infection of Mycobacterium tuberculosis
Secondary structure prediction of HutC regulators according to consensus sequences gave a higher number of β-strands towards the c-terminus, which is characteristic to HutC regulators (Figure 1) and the secondary structure prediction of MoyR revealed the same pattern (Figure 2A)
Two highly conserved leucine residues were found to be at the higher number of β-strands towards the c-terminus, which is characteristic to HutC regulators (Figure 1) and the secondary structure prediction of MoyR revealed the same pattern (Figure 2A)
Summary
Tuberculosis (TB), a disease that has plagued humankind throughout history, is caused mainly by the infection of Mycobacterium tuberculosis. It has been hypothesized that the genus Mycobacterium originated 150 million years ago, and the modern M. tuberculosis strain survived over 70,000 years, claiming millions of lives each year [1,2]. Even though antitubercular chemotherapy is the backbone of TB treatment, deaths due to the emergence of new strains of M. tuberculosis that are resistant to some or all antitubercular drugs (multi-drug resistant TB, MDR-TB) currently form a major health problem. Even decades after Koch’s findings, new genetic and molecular insights are still required to divulge the mechanisms involved in the acquisition of drug resistance and the survival of bacteria under stress in the environment. Adaptation to stress responses is primarily mediated through the tight regulation of gene expression, where transcriptional regulators play a fundamental role in the bacterial cell. The genome of M. tuberculosis encodes more than one hundred putative transcriptional regulators, out of which many need to be characterized
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