Skip to main content


Log in

Structure-based design of diverse inhibitors of Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase: combined molecular docking, dynamic simulation, and biological activity

  • Original Paper
  • Published:
Journal of Molecular Modeling Aims and scope Submit manuscript


Persistent nature of Mycobacterium tuberculosis is one of the major factors which make the drug development process monotonous against this organism. The highly lipophilic cell wall, which constituting outer mycolic acid and inner peptidoglycan layers, acts as a barrier for the drugs to enter the bacteria. The rigidity of the cell wall is imparted by the peptidoglycan layer, which is covalently linked to mycolic acid by arabinogalactan. Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) serves as the starting material in the biosynthesis of this peptidoglycan layers. This UDP-GlcNAc is synthesized by N-acetylglucosamine-1-phosphate uridyltransferase (GlmUMtb), a bi-functional enzyme with two functional sites, acetyltransferase site and uridyltransferase site. Here, we report design and screening of nine inhibitors against UTP and NAcGlc-1-P of uridyltransferase active site of glmUMtb. Compound 4 was showing good inhibition and was selected for further analysis. The isothermal titration calorimetry (ITC) experiments showed the binding energy pattern of compound 4 to the uridyltransferase active site is similar to that of substrate UTP. In silico molecular dynamics (MD) simulation studies, for compound 4, carried out for 10 ns showed the protein-compound complex to be stable throughout the simulation with relative rmsd in acceptable range. Hence, these compounds can serve as a starting point in the drug discovery processes against Mycobacterium tuberculosis.

Superimposed structures of glmuMtb - compound 4 complex collected at various intervals during molecular dynamics simulations displaying the stability of the complex

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others


  1. World Health Organization. Global tuberculosis control. WHO 2014 report:

  2. Ormerod LP (2005) Multidrug-resistant tuberculosis (MDR-TB): epidemiology, prevention and treatment. Br Med Bull 73:17–24

    Article  Google Scholar 

  3. ZhangW JVC, Scherman MS, Mahapatra S, Crick D, Bhamidi S, Xin Y, McNeil MR, Ma Y (2008) Expression, essentiality, and a microtiter plate assay for mycobacterial GlmU, the bifunctional glucosamine-1-phosphate acetyltransferase and N-acetylglucosamine-1-phosphate uridyltransferase. Int J Biochem Cell Biol 40:2560–2571

    Article  Google Scholar 

  4. Olsen LR, Vetting MW, Roderick SL (2007) Structure of the E. coli bifunctional GlmU acetyltransferase active site with substrates and products. Protein Sci 16:1230–1235

    Article  CAS  Google Scholar 

  5. Zhang Z, Bulloch EM, Bunker RD, Baker EN, Squire CJ (2009) Structure and function of GlmU from Mycobacterium tuberculosis. Acta Crystallogr D Biol Crystallogr 65:275–283

    Article  CAS  Google Scholar 

  6. Mio T, Yabe T, Arisawa M, Yamada-Okabe H (1998) The eukaryotic UDP-N-acetylglucosamine pyrophosphorylases gene cloning, protein expression, and catalytic mechanism. J Biol Chem 273:14392–14397

    Article  CAS  Google Scholar 

  7. Mio T, Yamada-Okabe T, Arisawa M, Yamada-Okabe H (1999) Saccharomyces cerevisiae GN’A1, an essential gene encoding a novel acetyltransferase involved in UDP-N-acetylglucosamine synthesis. J Biol Chem 274:424–429

    Article  CAS  Google Scholar 

  8. Verma SK, Jaiswal M, Kumar N, Parikh A, Nandicoori VK, Prakash B (2009) Structure of N-acetylglucosamine-1-phosphate uridyltransferase (GlmU) from Mycobacterium tuberculosis in a cubic space group. Acta Crystallogr Sect F: Struct Biol Cryst Commun 65:435–439

    Article  CAS  Google Scholar 

  9. Singh VK, Das K, Seshadri K (2012) Kinetic modelling of GlmU reactions–prioritization of reaction for therapeutic application. PLoS One 7, e43969

    Article  CAS  Google Scholar 

  10. Mochalkin I, Lightle S, Zhu Y, Ohren JF, Spessard C, Chirgadze NY, McDowell L (2007) Characterization of substrate binding and catalysis in the potential antibacterial target N-acetylglucosamine-1-phosphate uridyltransferase (GlmU). Protein Sci 16:2657–2666

    Article  CAS  Google Scholar 

  11. Jagtap PK, Verma SK, Vithani N, Bais VS, Prakash B (2013) Crystal structures identify an atypical two-metal-ion mechanism for uridyltransfer in GlmU: its significance to sugar nucleotidyl transferases. J Mol Biol 425:1745–1759

    Article  CAS  Google Scholar 

  12. Schrödinger Suite 2012 Protein Preparation Wizard; Epik v2.3, Impact v5.7, Prime v2.3, Glide v5.8, LigPrep v2.5, ConfGen v2.3 Schrödinger, LLC, New York, NY

  13. Olsson MHM, Søndergard CR, Rostkowski M, Jensen JH (2011) PROPKA3: consistent treatment of internal and surface residues in empirical p K a predictions. J Chem Theory Comput 7:525–537

    Article  CAS  Google Scholar 

  14. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461

    CAS  Google Scholar 

  15. Verdonk ML, Cole JC, Hartshorn MJ, Murray CW, Taylor RD (2003) Improved protein–ligand docking using GOLD. Proteins: Struct, Funct, Bioinf 52:609–623

    Article  CAS  Google Scholar 

  16. Schrödinger Suite 2012 Induced Fit Docking protocol; Glide v5.8, Prime v3.1, Schrödinger, LLC, New York, NY

  17. Schrödinger Suite 2012 QM-Polarized Ligand Docking protocol; Glide v5.8, Jaguar v7, QSite v5.8, Schrödinger, LLC, New York, NY

  18. Beard H, Cholleti A, Pearlman D, Sherman W, Loving KA (2013) Applying physics-based scoring to calculate free energies of binding for single amino acid mutations in protein-protein complexes. PLoS One 8, e82849

    Article  Google Scholar 

  19. Lyne PD, Lamb ML, Saeh JC (2006) Accurate prediction of the relative potencies of members of a series of kinase inhibitors using molecular docking and MM-GBSA scoring. J Med Chem 49:4805–4808

    Article  CAS  Google Scholar 

  20. Jagtap PKA, Soni V, Vithani N, Jhingan GD, Bais VS, Nandicoori VK, Prakash B (2012) Substrate-bound crystal structures reveal features unique to Mycobacterium tuberculosis N-acetyl-glucosamine 1-phosphate uridyltransferase and a catalytic mechanism for acetyl transfer. J Biol Chem 287:39524–39537

    Article  Google Scholar 

  21. Jorgensen WL, Maxwell DS, Tirado-Rives J (1996) Development and testing of the OPLS all-atom force field on conformational energetics and properties of organic liquids. J Am Chem Soc 118:11225–11236

    Article  CAS  Google Scholar 

  22. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  23. Kräutler V, van Gunsteren WF, Hünenberger PH (2001) A fast SHAKE algorithm to solve distance constraint equations for small molecules in molecular dynamics simulations. J Comput Chem 22:501–508

    Article  Google Scholar 

  24. QikProp v3.5, Schrödinger, LLC, New York, NY

  25. Parikh A, Verma SK, Khan S, Prakash B, Nandicoori VK (2009) PknB-mediated phosphorylation of a novel substrate, N-acetylglucosamine-1-phosphate uridyltransferase, modulates its acetyltransferase activity. J Mol Biol 386:451–464

    Article  CAS  Google Scholar 

Download references


The authors would like to thank the OSDD (Open Source Drug Discovery, India) consortium for funding the project.

Author information

Authors and Affiliations



Corresponding author

Correspondence to Perumal Yogeeswari.

Additional information

Vijay Soni and Priyanka Suryadevara contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Soni, V., Suryadevara, P., Sriram, D. et al. Structure-based design of diverse inhibitors of Mycobacterium tuberculosis N-acetylglucosamine-1-phosphate uridyltransferase: combined molecular docking, dynamic simulation, and biological activity. J Mol Model 21, 174 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: