Abstract
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 IDDPtkA had a greater inhibitory effect on the catalytic activity of KCDPtkA 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.
Highlights
Mycobacterium tuberculosis (M.tb) is an infectious agent that causes tuberculosis (TB) which is an airborne disease that affects almost one third of the world population
The catalytic activity of KCDPtkA alone is greater than the catalytic activity of KCDPtkA measured along with IDDPtkA, which suggests an inhibitory role of IDDPtkA for the catalytic activity of PtkA12
The quality of the modelled structures was validated through Protein Server Validation Suite (PSVS)[14] and the highest quality model was selected on the basis of Ramachandran analysis of ψ/φ angle from PROCHECK
Summary
Mycobacterium tuberculosis (M.tb) is an infectious agent that causes tuberculosis (TB) which is an airborne disease that affects almost one third of the world population. The process of drug development, which includes a series of steps starting from pre-clinical studies to clinical trials, is time, cost, and labor extensive. This has resulted in a lack of new molecules that could be further developed and approved by the FDA for successful incorporation into anti-TB treatment strategies. M.tb possesses various signal transduction mechanisms that include eleven two-component systems, eleven eukaryotic-like Ser/Thr protein kinases (PknA-PknL)[4], two protein tyrosine (Tyr) phosphatases (PtpA and PtpB) and a recently discovered protein tyrosine kinase (PtkA)[5,6] These signaling molecules block the host defense pathway and allow the bacteria to adapt and survive within the host macrophages[7]. Molecular docking and simulations were performed with FDA-approved drugs against PtkA (IDDPtkA-KCDPtkA) to identify potential M.tb PtkA inhibitors
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