Abstract
AbstractTuberculosis causes more than two million deaths per year. Faced with this global threat it is crucial to better understand the physiology of the causative organism, Mycobacterium Tuberculosis, in order to develop efficient therapeutic strategies. PKnB from Mycobacterium tuberculosis is a crucial receptor-like protein kinase involved in signal transduction. M. tuberculosis PKnB is a trans-membrane Ser/Thr protein kinase (STPK) highly conserved in Gram-positive bacteria and apparently essential for Mycobacterial viability. We have attempted with the help of virtual screening and docking approaches to expound the extent of specificity of protein kinase B towards different classes of Thiadiazoles (an anti-tubercular agent). The selected Thiadiazoles were selected on the basis of the structural specificity to the enzyme towards its substrate and inhibitors. Total number of Thiadiazoles were 5000 in number with the minimum binding energy of -10.46 kcal/mol with 10 molecules showing hydrogen bonds with the active site residue. The protein kinase B peptide contains two types of structural elements (Valine 95, Arginine 97) and the basic residue ring consisted of glycine rich residues. The structure of the protein-ligand complex reveals that Thiadiazoles partially occupies the adenine-binding pocket in PKnB, providing a framework for the design of compounds with potential therapeutic applications. The study provides hints for the future design of new derivatives with higher potency and specificity.
Highlights
The knack of Mycobacterium tuberculosis, pathogen liable for Tuberculosis (TB), to adapt to the changing environmental conditions requires an efficient way of sensing and transducing extracellular signals [1]
One of the mechanisms used in Mycobacteria to assure a tight regulation of cell growth and division involves the reversible phosphorylation on serine/threonine residues, a well-established process for eukaryotic signaling networks [2]
[10] Here we report that thiadiazole, a compound reported as anti-microbial [10,11,12,13] and anti-tubercular agent [14,15,16,17,18] is a PKnB inhibitor capable of preventing mycobacterial cell growth, suggesting that bacterial kinases may represent a potential target for drug design and derivatives of Thiazdiazoles exhibit a property of inhibiting mycobacterial growth
Summary
The knack of Mycobacterium tuberculosis, pathogen liable for Tuberculosis (TB), to adapt to the changing environmental conditions requires an efficient way of sensing and transducing extracellular signals [1]. The crystal structure of the kinase domain of PknB in complex with an ATP analogue [4] and [5] showed a striking conservation of both protein fold and catalytic mechanism between eukaryotic and prokaryotic STPKs. Earlier it was shown that PKnB is regulated by autophosphorylation and dephosphorylation by the Ser/Thr protein phosphatase [6] and [7] and recent work showed that PKnB is predominantly expressed during exponential growth, where its over expression causes morphological changes linked to defects in cell wall synthesis and cell division [8]. The structure of the protein-ligand complex shows that Thiadiazole derivatives bound to the structural element (VAL 95) of PKnB from MTB partially occupies the adeninebinding pocket in PKnB and is an ATP-competitive inhibitor of PKnB and suggests a mode of regulation of protein kinases in mycobacteria
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
