Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors

Abstract

BackgroundTuberculosis has become a major health problem being the second leading cause of death worldwide. Mycobacterium tuberculosis secretes a virulence factor, protein tyrosine phosphatase B (mPTPB) in the cytoplasm of host macrophage which suppresses its natural innate immune response and helps the pathogen survive and proliferate in the phagosome. The present study aims at indentifying potent inhibitors of mPTPB by using computational approaches of ligand based molecular modeling and docking studies.ResultsA 3D QSAR model was developed using a set of benzofuran salicylic acid based mPTPB inhibitors with experimentally known IC50 values. The model was generated using the statistical method of principle component regression analysis in combination with step wise forward variable selection algorithm. It was observed that steric and hydrophobic descriptors positively contribute towards the inhibitory activity of the ligands. The developed model had a robust internal as well as external predictive power as indicated by the q2 value of 0.8920 and predicted r2 value of 0.8006 respectively. Hence, the generated model was used to screen a large set of naturally occurring chemical compounds and predict their biological activity to identify more potent natural compounds targeting mPTPB. The two top potential hits (with pIC50 value of 1.459 and 1.677 respectively) had a similar interaction pattern as that of the most potent compound (pIC50 = 1.42) of the congeneric series.ConclusionThe contour plot provided a better understanding of the relationship between structural features of substituted benzofuran salicylic acid derivatives and their activities which would facilitate design of novel mPTPB inhibitors. The QSAR modeling was used to obtain an equation, correlating the important steric and hydrophobic descriptors with the pIC50 value. Thus, we report two natural compounds of inhibitory nature active against mPTPB enzyme of Mycobacterium tuberculosis. These inhibitors have the potential to evolve as lead molecules in the development of drugs for the treatment of tuberculosis.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2164-15-S1-S3) contains supplementary material, which is available to authorized users.

Mechanistic analysis elucidating the relationship between Lys96 mutation in Mycobacterium tuberculosispyrazinamidase enzyme and pyrazinamide susceptibility

“…Treatment of drug-resistant tuberculosis is hampered by poor efficacy and high toxicity of the second-line drugs [ 4 ]. Continuous efforts are being made worldwide to find out some novel protein targets against which new effective drugs can be designed [ 5 , 6 ].…”

Double Mutants in DNA Gyrase Lead to Ofloxacin Resistance in Mycobacterium tuberculosis

“…Molecular docking was initiated by generating grid file using receptor grid generation panel of Glide [Friesner et al, ; Halgren et al, ; Dhanjal et al, ] and AutoDock 4.2.6 [Morris et al, ]. Keeping both receptor and ligand molecules flexible, extra precision (XP) docking was performed for wild and double mutants GyrA A90V GyrB D500N and GyrA A90V GyrB T539N .…”

Expression of Mycobacterium tuberculosis Protein Tyrosine Phosphatase B in Escherichia coli and Its Recovery from Inclusion Body

“…We have also successfully overexpressed PtpB under T7 promoter and IPTG induction in Escherichia coli BL21(DE3) cells first in the form of inclusion body and further re-solubilize it into its active form. This result thus provides materials in order to investigate the biochemical property of PtpB, as well as assaying inhibitory potential of several PtpB inhibitor candidates resulted from computational analysis recently reported (Dhanjal et al, 2014).…”

“…Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB). By using this result to produce functional PtpB, it is tempting in the future to test the potencies of several chemical agents resulted from in silico study (Dhanjal et al, 2014) to inhibit PtpB both in vitro and in vivo. Of equally important, screening of inhibitory effect of new compounds from a chemical library or new sources might also pave a way to find drug leads (Chen et al, 2016;He et al, 2015).…”