Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Molecular docking and in silico studies on analogues of 2-methylheptyl isonicotinate with DHDPS enzyme of Mycobacterium tuberculosis

  • 372 Accesses

  • 1 Citations


Mycobacterium tuberculosis and other strains of mycobacteria cause tuberculosis which has infected one-third of the world’s population. Moreover, there has been increase in multidrug-resistant strains which spotlights the need for a new anti-tuberculosis drug. The cell wall of mycobacteria is characterised by high diaminopimelic acid (DAP) content—an intermediate of the (S)-lysine biosynthetic pathway and dihydrodipicolinate synthase (DHDPS) enzyme catalyses the first unique reaction of this biosynthesis. Interestingly, the gene knockout experiment demonstrates the essentiality of the DAP pathway, where the absence of DAP results in cell lysis and death. Because of this importance, any inhibitor of DHDPS enzyme may indicate a new class of anti-tubercular agent. In this perspective, the aim of the present study is to focus on the molecular docking analysis of DHDPS enzyme against the analogues of 2-methylheptyl isonicotinate—a compound having strong antibacterial property against Mycobacterium tuberculosis. The analogues used in the present study were retrieved from the NCBI PubChem database subject to Lipinski rule of five filters which would make the analogues like an orally active drug. Further, the top docked compounds at the active site of the DHDPS enzyme were analysed for ADME-Toxicity prediction.

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

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


  1. ACD/I-Lab (2000) Version 2.0. Advanced Chemistry Development, Inc., Toronto

  2. Blagova E, Levdikov V, Milioti N, Fogg MJ, Kalliomaa AK, Brannigan JA, Wilson KS, Wilkinson AJ (2006) Crystal structure of dihydrodipicolinate synthase (BA3935) from Bacillus anthracis at 1.94: a resolution. Proteins 62:297

  3. Blickling S, Beisel HG, Bozic D, Knablein J, Laber B, Huber R (1997) Structure of dihydrodipicolinate synthase of Nicotiana sylvestris reveals novel quaternary structure. J Mol Biol 274:608–621

  4. Bolton E, Wang Y, Thiessen PA, Bryant SH (2008) PubChem: integrated platform of small molecules and biological activities. In: Annual reports in computational chemistry, vol 4, chap 12. American Chemical Society, Washington

  5. Bordoloi GN, Kumari B, Guha A, Bordoloi M, Yadav RNS, Manoj KR, Bora TC (2001) Isolation and structure elucidation of a new antifungal and antibacterial antibiotic produced by Streptomycin sp. 201. Biosci Biotechnol Biochem 65:1856–1858

  6. Boruwa J, Kalita B, Barua NC, Borah JC, Mazumder S, Thakur D, Gogoi DK, Bora TC (2004) Synthesis, absolute stereochemistry and molecular designof the new antifungal and antibacterial antibiotic produced by Streptomyces sp. 201. Bioorg Med Chem 14:3571–3574

  7. Burgess BR, Dobson RC, Dogovski C, Jameson GB, Parker MW, Perugini MA (2008) Purification, crystallization and preliminary X-ray diffraction studies to near-atomic resolution of dihydrodipicolinate synthase from methicillin-resistant Staphylococcus aureus. Acta Crystallogr F 64:659–661

  8. ChemOffice (2010) CambridgeSoft Corporation. Cambridge, MA

  9. Cox RJ, Sutherland A, Vederas JC (2000) Bacterial diaminopimelate metabolism as a target for antibiotic design. Bioorg Med Chem Lett 8:843–871

  10. Dobson RCJ, Valegard K, Gerrard JA (2004) The crystal structure of three site-directed mutants of Escherichia coli dihydrodipicolinate synthase: further evidence for a catalytic triad. J Mol Biol 338:329–339

  11. Freitas MP (2006) MIA-QSAR modelling of anti-HIV-1 activities of some 2-amino-6- arylsulfonylbenzonitriles and their thio and sulfinyl congeners. Org Biomol Chem 4:1154–1159

  12. Frisch DA, Gengenbach BG, Tommey AM, Sellner JM, Somers DA, Myers DE (1991) Isolation and characterization of dihydrodipicolinate synthase from maize. Plant Physiol 96:444–452

  13. Garg A, Tewari R, Raghava GPS (2010) Virtual Screening of potential druglike inhibitors against Lysine/DAP pathway of Mycobacterium tuberculosis. BMC Bioinformat II 18(11 Suppl 1):S53

  14. Hutton CA, Southwood TJ, Turner JJ (2003) Inhibitors of lysine biosynthesis as antibacterial agents. Mini Rev Med Chem 3:115–127

  15. Hutton CA, Perugini MA, Gerrard JA (2007) Inhibition of lysine biosynthesis: an evolving antibiotic Strategy. Mol BioSyst 3:458–465

  16. Jasmer RM, Nahid P, Hopewell PC (2002) N Engl J Med 347:1860–1866

  17. Kefala G, Evans GL, Griffin MD, Devenish SR, Pearce FG, Perugini MA, Gerrard JA, Weiss MS, Dobson RC (2008) Crystal structure and kinetic study of dihydrodipicolinate synthase from Mycobacterium tuberculosis. Biochem. J. 411:351–360

  18. Konstantinos A (2010) Testing for tuberculosis. Aust Prescrib 33:12–18

  19. Kumar V, Abbas AK, Fausto N, Mitchell RN (2007) Robbins basic pathology, 8th edn. Saunders Elsevier, Philadelphia, pp 516–522

  20. Kumpaisal R, Hashimoto T, Yamada Y (1987) Purification and characterization of Dihydrodipicolinate synthase from wheat suspension cultures. Plant Physiol 85:145–151

  21. Laber B, Gomis-Ruth FX, Romao MJ, Huber R (1992) Escherichia coli dihydrodipicolinate synthase: identification of the active site and crystallization. Biochem J 288:691–695

  22. Lipinski CA (2000) Drug-like properties and the causes of poor solubility and poor permeability. J Pharm Toxicol Methods 44:35–249

  23. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (1997) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 23:3–25

  24. Mitsakos V, Dobson RC, Pearce FG, Devenish SR, Evans GL, Burgess BR, Perugini MA, Gerrard JA, Hutton CA (2008) Inhibiting dihydrodipicolinate synthase across species: towards specificity for pathogens? Bioorg Med Chem Lett 18(2):842–844

  25. Molegro APS (2011) MVD 5.0 Molegro Virtual Docker. Aarhus C, Denmark

  26. Negrutin J, Cattoir-Reynearts A, Verbruggen J, Jacobs M (1984) Lysine overproducer mutants with an altered dihydrodipicolinate synthase from protoplast culture of Nicotiana sylvestris Spegazzini and Comes. Theor Appl Genet 68:11–20

  27. Pavelka Jr MS, Jacobs Jr WR (1996) Biosynthesis of diaminopimelate, the precursor of lysine and a component of peptidoglycan is an essential function of Mycobacterium smegmatis. J Bacteriol 78: 6496–6507

  28. WHO Report (2008) http://www.who.int/tb/publications/global_report/2008/summary/en/index.html

  29. Singh SP, Bezbaruah RL, Bora TC (2012) Molecular interaction of novel compound 2-methylheptyl isonicotinate produced by streptomyces sp. 201 with dihydrodipicolinate synthase (DHDPS) enzyme of Mycobacterium tuberculosis for its antibacterial activity. Ind J Microbiol. doi:10.1007/s12088-012-0252-4

  30. Thomsen R, Christensen MH (2006) MolDock: A New Technique for High-Accuracy Molecular Docking. J Med Chem 49:3315–3321

  31. Tripathi RP, Tewari N, Dwivedi N, Tiwari VK (2005) Fighting tuberculosis: an old disease with new challenges. Med Res Rev 25(1):93–131

  32. Tuberculosis (2007) World Health Organization 2007. http://who.int/mediacentre/factsheets/fs104/en/index.html

  33. Turner JJ, Gerrard JA, Hutton CA (2005a) Heterocyclic inhibitors of dihydrodipicolinate synthase are not competitive. Bioorg Med Chem 13:2133–2140

  34. Turner JJ, Healy JP, Dobson RC, Gerrard JA, Hutton CA (2005b) Two new irreversible inhibitors of dihydrodipicolinate synthase: diethyl (E, E)-4-oxo-2,5-heptadienedioate and diethyl (E)-4-oxo-2-heptenedioate. Bioorg Med Chem Lett 15:995–998

  35. Ulrich B, Norman LA (1982) Molecular mechanics (ACS Monograph 177). American Chemical Society, Washington, DC

  36. Wang Y, Bolton E, Dracheva S, Karapetyan K, Shoemaker SA, Suzek TO, Wang J, Xiao J, Zhang J, Bryant SH (2010) An overview of the PubChem BioAssay resource. Nucleic Acids Res 38:D255–D266

  37. World Health Organization “Epidemiology” (2009) Global tuberculosis control: epidemiology, strategy, financing, pp 6–33. http://who.int/entity/tb/publications/global_report/2009/pdf/chapter1.pdf

  38. World Health Organization, Global Tuberculosis Control (2007) Surveillance, planning, financing. World Health Organization, Geneva. http://www.who.int/tb/publications/global_report/2007/pdf/full.pdf

Download references


Salam Pradeep Singh thanks Dr. T. Madhan Mohan, Adviser, Department of Biotechnology, New Delhi, India for promoting Bioinformatics in North East India.

Author information

Correspondence to Salam Pradeep Singh.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Singh, S.P., Konwar, B.K., Bezbaruah, R.L. et al. Molecular docking and in silico studies on analogues of 2-methylheptyl isonicotinate with DHDPS enzyme of Mycobacterium tuberculosis . Med Chem Res 22, 4755–4765 (2013). https://doi.org/10.1007/s00044-013-0488-5

Download citation


  • DHDPS enzyme
  • Molecular docking
  • 2-Methylheptyl isonicotinate
  • ADME-toxicity