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Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis
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Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis
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Journal Article
Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis
2020
Overview
Tuberculosis (TB) is a leading cause of death worldwide and its impact has intensified due to the emergence of multi drug-resistant (MDR) and extensively drug-resistant (XDR) TB strains. Protein phosphorylation plays a vital role in the virulence of
Mycobacterium tuberculosis
(
M.tb
) mediated by protein kinases. Protein tyrosine phosphatase A (MptpA) undergoes phosphorylation by a unique tyrosine-specific kinase, protein tyrosine kinase A (PtkA), identified in the
M.tb
genome. PtkA phosphorylates PtpA on the tyrosine residues at positions 128 and 129, thereby increasing PtpA activity and promoting pathogenicity of MptpA. In the present study, we performed an extensive investigation of the conformational behavior of the intrinsically disordered domain (IDD) of PtkA using replica exchange molecular dynamics simulations. Long-term molecular dynamics (MD) simulations were performed to elucidate the role of IDD on the catalytic activity of kinase core domain (KCD) of PtkA. This was followed by identification of the probable inhibitors of PtkA using drug repurposing to block the PtpA-PtkA interaction. The inhibitory role of IDD on KCD has already been established; however, various analyses conducted in the present study showed that IDD
PtkA
had a greater inhibitory effect on the catalytic activity of KCD
PtkA
in the presence of the drugs esculin and inosine pranobex. The binding of drugs to PtkA resulted in formation of stable complexes, indicating that these two drugs are potentially useful as inhibitors of
M.tb
.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ Bacterial Proteins - antagonists & inhibitors
/ Bacterial Proteins - chemistry
/ Bacterial Proteins - metabolism
/ Esculin
/ Genomes
/ Humanities and Social Sciences
/ Inosine Pranobex - chemistry
/ Inosine Pranobex - pharmacology
/ Kinases
/ Molecular Dynamics Simulation
/ Mycobacterium tuberculosis - drug effects
/ Mycobacterium tuberculosis - metabolism
/ Mycobacterium tuberculosis - pathogenicity
/ Protein Binding - drug effects
/ Protein Tyrosine Phosphatases - chemistry
/ Protein Tyrosine Phosphatases - metabolism
/ Protein-Tyrosine Kinases - antagonists & inhibitors
/ Protein-Tyrosine Kinases - chemistry
/ Protein-Tyrosine Kinases - metabolism
/ Protein-tyrosine-phosphatase
/ Proteins
/ Science
