Identification of new benzamide inhibitor againstα-subunit of tryptophan synthase fromMycobacterium tuberculosisthrough structure-based virtual screening, anti-tuberculosis activity and molecular dynamics simulations

Abstract

Multi-drug-resistant tuberculosis and extensively drug-resistant tuberculosis has emerged as global health threat, causing millions of deaths worldwide. Identification of new drug candidates for tuberculosis (TB) by targeting novel and less explored protein targets will be invaluable for antituberculosis drug discovery. We performed structure-based virtual screening of eMolecules database against a homology model of relatively unexplored protein target: the α-subunit of tryptophan synthase (α-TRPS) from Mycobacterium tuberculosis essential for bacterial survival. Based on physiochemical properties analysis and molecular docking, the seven candidate compounds were selected and evaluated through whole cell-based activity against the H37Rv strain of M. tuberculosis. A new Benzamide inhibitor against α-subunit of tryptophan synthase (α-TRPS) from M. tuberculosis has been identified causing 100% growth inhibition at 25 μg/ml and visible bactericidal activity at 6 μg/ml. This benzamide inhibitor displayed a good predicted binding score (-48.24 kcal/mol) with the α-TRPS binding pocket and has logP value (2.95) comparable to Rifampicin. Further refinement of docking results and evaluation of inhibitor-protein complex stability were investigated through Molecular dynamic (MD) simulations studies. Following MD simulations, Root mean square deviation, Root mean square fluctuation and secondary structure analysis confirmed that protein did not unfold and ligand stayed inside the active pocket of protein during the explored time scale. This identified benzamide inhibitor against the α-subunit of TRPS from M. tuberculosis could be considered as candidate for drug discovery against TB and will be further evaluated for enzyme-based inhibition in future studies.

Indole‐3‐Glycerol Phosphate Synthase From Mycobacterium tuberculosis: A Potential New Drug Target

“…The final step in this pathway is catalyzed by tryptophan synthase and inhibition of this enzyme from M. tuberculosis (MtTRPS) with both previously known and novel TRPS inhibitors has been studied. [49][50][51][52][53][54] Inhibition of MtIGPS by novel compounds, however, remains largely unexplored. Yang and co-workers reported that MtIGPS is significantly inhibited by the antibiotics streptomycin, kanamycin, and geomycine.…”

Discovery of antimicrobial agent targeting tryptophan synthase

“…9 Because a functional tryptophan synthase (TRPS) is required for the survival of bacteria in vivo and higher animals and humans do not have comparable L-Trp biosynthetic machinery, RPS is a highly specific drug target. 6,[10][11][12][13] Our study focused on inhibiting the function of TRPS, a bienzyme complex that catalyzes the last two steps of tryptophan biosynthesis. TRPS is a heterodimer, but in a biological setting, it exists as a tetramer, and the two dimers connect linearly with two β subunits attached to each other (Figure 1a).…”

Targeting amino acid metabolism of Mycobacterium tuberculosis for developing inhibitors to curtail its survival

“…In addition, benzamide C2 exerts complete bactericidal activity of Mtb H37Rv at 25 μg/ml and partial inhibition of bacterial growth at 6 μg/ml concentrations. The inhibitor associates with binding pocket of trpA at R221 through formation of hydrogen bonds 13 …”