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.
Subject(s)
Bacterial Proteins/metabolism , Esculin/pharmacology , Inosine Pranobex/pharmacology , Mycobacterium tuberculosis/drug effects , Protein Tyrosine Phosphatases/metabolism , Protein-Tyrosine Kinases/metabolism , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/chemistry , Drug Repositioning , Esculin/chemistry , Inosine Pranobex/chemistry , Models, Molecular , Molecular Dynamics Simulation , Mycobacterium tuberculosis/metabolism , Mycobacterium tuberculosis/pathogenicity , Phosphorylation , Protein Binding/drug effects , Protein Conformation , Protein Domains , Protein Tyrosine Phosphatases/chemistry , Protein Unfolding , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/chemistryABSTRACT
In vivo magnetic resonance techniques such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy have been some of the most useful tools for evaluation of neurologic diseases. In subacute sclerosing panencephalitis, magnetic resonance spectroscopy can be an additional tool for evaluation of disease progression or the efficacy of the treatment, such as interferon or inosiplex, compared with MRI. Inosiplex is one of the effective drugs for subacute sclerosing panencephalitis, but our in vivo and in vitro magnetic resonance spectroscopic study indicated that inosiplex affects the spectra, suggesting a possible failure of neurologic evaluation in a patient with subacute sclerosing panencephalitis treated with inosiplex.
