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. 2020 Mar 10;10(1):4413.
doi: 10.1038/s41598-020-61132-w.

Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis

Priya Nagpal  1 , Salma Jamal  2 , Hina Singh  2 , Waseem Ali  2 , Sana Tanweer  2 , Rahul Sharma  2 , Abhinav Grover  3 , Sonam Grover  4
Affiliations

Long-range replica exchange molecular dynamics guided drug repurposing against tyrosine kinase PtkA of Mycobacterium tuberculosis

Priya Nagpal et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Depicts the plot of (A) RMSD and (B) secondary structure elements in IDDPtkA.
Figure 2
Figure 2
Snapshots of IDD taken at every 2.5 ns during 50 ns MD simulations.
Figure 3
Figure 3
Illustrate interaction pattern between IDD and KCD domains of PtkA; IDDPtkA (magenta), KCDPtkA (cyan), hydrogen bonds (yellow), hydrophobic residues (orange).
Figure 4
Figure 4
Represents the plots obtained during MD simulations of unbound and drug-bounded PtkA (A) RMSD (B) Rg (C) SASA (D) RMSF; PtkA (red), PtkA-esculin (purple) and PtkA-inosine pranobex (green).
Figure 5
Figure 5
Hydrogen bonding pattern of the drugs (magenta), esculin and inosine pranobex, with PtkA (cyan).
Figure 6
Figure 6
Projection of motion of protein atoms of (A) PtkA, (B) PtkA-esculin and (C) PtkA-inosine pranobex on PC1 and PC2.
Figure 7
Figure 7
Shows the diagonalized covariance matrix of (A) PtkA (B) PtkA-esculin and (C) PtkA-inosine pranobex.
Figure 8
Figure 8
Shows the Gibbs free energy landscape plot of (A) PtkA and (B) PtkA-esculin and (C) PtkA-inosine pranobex.
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