Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Research Article

Structure-based Discovery of Narirutin as a Shikimate kinase Inhibitor with Anti-tubercular Potency

Author(s): Pramod Kumar Sahu, Pranab Kishor Mohapatra*, Dhanji Popatbhai Rajani and Mukesh Kumar Raval*

Volume 16, Issue 5, 2020

Page: [523 - 529] Pages: 7

DOI: 10.2174/1573409915666191025112150

Price: $65

Abstract

Background: Shikimate pathway is essential for tubercular bacillus but it is absent in mammals. Therefore, Shikimate kinase and other enzymes in the pathway are potential targets for the development of novel anti-tuberculosis drugs.

Objective: In the present study, Shikimate kinase is selected as the target for in silico screening of phytochemicals with an aim to discover a novel herbal drug against Mycobacterium tuberculosis (Mtb).

Methods: A structure-based drug discovery approach is undertaken for the execution of the objective. Virtual screening of phytochemical database NPACT against the target, Shikimate kinase (PDB ID 3BAF), is carried out followed by toxicity and drug-likeness filtration. Finally, a lead, narirutin was selected for in vitro anti-tubercular study.

Results: Narirutin, present in citrus fruits, emerges as the lead. It is considered to be non-toxic with predicted high LD50 value, 12000 mg/kg body weight. The phytochemical is tested for its antitubercular activity in vitro. It has MIC99 62.5 μg/mL against the MtbH37Rv strain.

Conclusion: This is the first-ever report to show anti-tuberculosis potency of narirutin.

Keywords: Molecular docking, Mycobacterium tuberculosis, narirutin, shikimate kinase, drug-likeness, toxicity.

Graphical Abstract
[1]
Koch, A.; Mizrahi, V. Mycobacterium tuberculosis. Trends Microbiol., 2018, 26(6), 555-556.
[http://dx.doi.org/10.1016/j.tim.2018.02.012] [PMID: 29580884]
[2]
Rock, R.B.; Olin, M.; Baker, C.A.; Molitor, T.W.; Peterson, P.K. Central nervous system tuberculosis: pathogenesis and clinical aspects. Clin. Microbiol. Rev., 2008, 21(2), 243-261.
[http://dx.doi.org/10.1128/CMR.00042-07] [PMID: 18400795]
[3]
Thwaites, G.E.; van Toorn, R.; Schoeman, J. Tuberculous meningitis: more questions, still too few answers. Lancet Neurol., 2013, 12(10), 999-1010.
[http://dx.doi.org/10.1016/S1474-4422(13)70168-6] [PMID: 23972913]
[4]
Revised National TB Control Programme Annual Status Report, India http://www.tbcindia.gov.in
[5]
World Health Organization. Global Tuberculosis Report 2015 http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf (2015)
[6]
World Health Organization. Global Tuberculosis Report 2016 http://apps.who.int/iris/bitstream/10665/250441/1/9789241565394-eng.pdf OCLC: 961271202 (2016)
[7]
Dicks, K.V.; Stout, J.E. Molecular diagnostics for mycobacterium tuberculosis infection. Annu. Rev. Med., 2019, 70, 11-14.
[http://dx.doi.org/10.1146/annurev-med-040717-051502]
[8]
Zhang, Y.; Amzel, L.M. Tuberculosis drug targets. Curr. Drug Targets, 2002, 3(2), 131-154.
[http://dx.doi.org/10.2174/1389450024605391] [PMID: 11958297]
[9]
Bentley, R. The shikimate pathway a metabolic tree with many branches. Crit. Rev. Biochem. Mol. Biol., 1990, 25(5), 307-384.
[http://dx.doi.org/10.3109/10409239009090615] [PMID: 2279393]
[10]
Duncan, K. Identification and validation of novel drug targets in tuberculosis. Curr. Pharm. Des., 2004, 10(26), 3185-3194.
[http://dx.doi.org/10.2174/1381612043383223] [PMID: 15544508]
[11]
Segura-Cabrera, A.; Rodríguez-Pérez, M.A. Structure-based prediction of Mycobacterium tuberculosis Shikimate kinase inhibitors by high-throughput virtual screening. Bioorg. Med. Chem. Lett., 2008, 18(11), 3152-3157.
[http://dx.doi.org/10.1016/j.bmcl.2008.05.003] [PMID: 18486472]
[12]
Sahu, P.K.; Raval, M.K. Search of novel anti-tubercular drug by virtual screening of ligands against EPSP synthase enzyme from Mycobacterium tuberculosis. Pharm. Biol. Eval., 2016, 3, 520-527.
[13]
Bansal, R.; Sharma, D.; Singh, R. Tuberculosis and its treatment: an overview. Mini Rev. Med. Chem., 2018, 18(1), 58-71.
[PMID: 27553018]
[14]
Bishi, L.Y.; Vedithi, S.C.; Blundell, T.L.; Mugumbate, G. Computational deorphaning of Mycobacterium tuberculosis targets; Intec Open, 2019.
[15]
Davies, G.M.; Barrett-Bee, K.J.; Jude, D.A.; Lehan, M.; Nichols, W.W.; Pinder, P.E.; Thain, J.L.; Watkins, W.J.; Wilson, R.G. (6S)-6-fluoroshikimic acid, an antibacterial agent acting on the aromatic biosynthetic pathway. Antimicrob. Agents Chemother., 1994, 38(2), 403-406.
[http://dx.doi.org/10.1128/AAC.38.2.403] [PMID: 8192477]
[16]
Oliveira, J.S.; Pinto, C.A.; Basso, L.A.; Santos, D.S. Cloning and overexpression in soluble form of functional Shikimate kinase and 5-enolpyruvylshikimate 3-phosphate synthase enzymes from Mycobacterium tuberculosis. Protein Expr. Purif., 2001, 22(3), 430-435.
[http://dx.doi.org/10.1006/prep.2001.1457] [PMID: 11483005]
[17]
Zhang, X.; Zhang, S.; Hao, F.; Lai, X.; Yu, H.; Huang, Y.; Wang, H. Expression, purification and properties of shikimate dehydrogenase from Mycobacterium tuberculosis. J. Biochem. Mol. Biol., 2005, 38(5), 624-631.
[PMID: 16202245]
[18]
Pereira, J.H.; Vasconcelos, I.B.; Oliveira, J.S.; Caceres, R.A.; de Azevedo, W.F., Jr; Basso, L.A.; Santos, D.S. Shikimate kinase: a potential target for development of novel antitubercular agents. Curr. Drug Targets, 2007, 8(3), 459-468.
[http://dx.doi.org/10.2174/138945007780059013] [PMID: 17348838]
[19]
Pereira, J.H.; de Oliveira, J.S.; Canduri, F.; Dias, M.V.B.; Palma, M.S.; Basso, L.A.; Santos, D.S.; de Azevedo, W.F. Jr Structure of Shikimate kinase from Mycobacterium tuberculosis reveals the binding of shikimic acid. Acta Crystallogr. D Biol. Crystallogr, 2004, 60((Pt 12 Pt 2)), 2310-2319.
[http://dx.doi.org/10.1107/S090744490402517X] [PMID: 15583379]
[20]
Krell, T.; Coggins, J.R.; Lapthorn, A.J. The three-dimensional structure of shikimate kinase. J. Mol. Biol., 1998, 278(5), 983-997.
[http://dx.doi.org/10.1006/jmbi.1998.1755] [PMID: 9600856]
[21]
Krell, T.; Maclean, J.; Boam, D.J.; Cooper, A.; Resmini, M.; Brocklehurst, K.; Kelly, S.M.; Price, N.C.; Lapthorn, A.J.; Coggins, J.R. Biochemical and X-ray crystallographic studies on shikimate kinase: the important structural role of the P-loop lysine. Protein Sci., 2001, 10(6), 1137-1149.
[http://dx.doi.org/10.1110/ps.52501] [PMID: 11369852]
[22]
Gu, Y.; Reshetnikova, L.; Li, Y.; Wu, Y.; Yan, H.; Singh, S.; Ji, X. Crystal structure of Shikimate kinase from Mycobacterium tuberculosis reveals the dynamic role of the LID domain in catalysis. J. Mol. Biol., 2002, 319(3), 779-789.
[http://dx.doi.org/10.1016/S0022-2836(02)00339-X] [PMID: 12054870]
[23]
Dhaliwal, B.; Nichols, C.E.; Ren, J.; Lockyer, M.; Charles, I.; Hawkins, A.R.; Stammers, D.K. Crystallographic studies of shikimate binding and induced conformational changes in Mycobacterium tuberculosis shikimate kinase. FEBS Lett., 2004, 574(1-3), 49-54.
[http://dx.doi.org/10.1016/j.febslet.2004.08.005] [PMID: 15358538]
[24]
Gan, J.; Gu, Y.; Li, Y.; Yan, H.; Ji, X. Crystal structure of Mycobacterium tuberculosis Shikimate kinase in complex with shikimic acid and an ATP analogue. Biochemistry, 2006, 45(28), 8539-8545.
[http://dx.doi.org/10.1021/bi0606290] [PMID: 16834327]
[25]
Hartmann, M.D.; Bourenkov, G.P.; Oberschall, A.; Strizhov, N.; Bartunik, H.D. Mechanism of phosphoryl transfer catalyzed by Shikimate kinase from Mycobacterium tuberculosis. J. Mol. Biol., 2006, 364(3), 411-423.
[http://dx.doi.org/10.1016/j.jmb.2006.09.001] [PMID: 17020768]
[26]
Laskowski, R.A.; Hutchinson, E.G.; Michie, A.D.; Wallace, A.C.; Jones, M.L.; Thornton, J.M. PDBsum: a Web-based database of summaries and analyses of all PDB structures. Trends Biochem. Sci., 1997, 22(12), 488-490.
[http://dx.doi.org/10.1016/S0968-0004(97)01140-7] [PMID: 9433130]
[27]
Sahu, P.K.; Raval, M.K. Virtual screening for inhibitors of Shikimate kinase of Mycobacterium tuberculosis. Phram. Biol. Eval., 2016, 3, 320-326.
[28]
Laskowski, R.A.; Swindells, M.B. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. J. Chem. Inf. Model., 2011, 51(10), 2778-2786.
[http://dx.doi.org/10.1021/ci200227u] [PMID: 21919503]
[29]
Mangal, M.; Sagar, P.; Singh, H.; Raghava, G.P.S.; Agarwal, S.M. NPACT: naturally occurring plant-based anti-cancer compound-activity-target database. Nucleic Acids Res., 2013, 41(Database issue), D1124-D1129.
[http://dx.doi.org/10.1093/nar/gks1047] [PMID: 23203877]
[30]
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem., 2010, 31(2), 455-461.
[PMID: 19499576]
[31]
Yang, J-M.; Chen, C-C. GEMDOCK: a generic evolutionary method for molecular docking. Proteins, 2004, 55(2), 288-304.
[http://dx.doi.org/10.1002/prot.20035] [PMID: 15048822]
[32]
Wang, R.; Lai, L.; Wang, S. Further development and validation of empirical scoring functions for structure-based binding affinity prediction. J. Comput. Aided Mol. Des., 2002, 16(1), 11-26.
[http://dx.doi.org/10.1023/A:1016357811882] [PMID: 12197663]
[33]
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J. Comput. Chem., 2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID: 19399780]
[34]
Labbé, C.M.; Rey, J.; Lagorce, D.; Vavruša, M.; Becot, J.; Sperandio, O.; Villoutreix, B.O.; Tufféry, P.; Miteva, M.A. MTiOpenScreen: a web server for structure-based virtual screening. Nucleic Acids Res., 2015, 43(W1)W448-54
[http://dx.doi.org/10.1093/nar/gkv306] [PMID: 25855812]
[35]
Hsu, K.C.; Chen, Y.F.; Lin, S-R.; Yang, J.M. iGEMDOCK: a graphical environment of enhancing GEMDOCK using pharmacological interactions and post-screening analysis. BMC Bioinformatics, 2011, 12(Suppl. 1), S33.
[http://dx.doi.org/10.1186/1471-2105-12-S1-S33] [PMID: 21342564]
[36]
Drwal, M.N.; Banerjee, P.; Dunkel, M.; Wettig, M.R.; Preissner, R. ProTox: a web server for the in silico prediction of rodent oral toxicity. Nucleic Acids Res, 2014, 42(Web Server issue), W53-8.
[http://dx.doi.org/10.1093/nar/gku401] [PMID: 24838562]
[37]
Ahmed, J.; Worth, C.L.; Thaben, P.; Matzig, C.; Blasse, C.; Dunkel, M.; Preissner, R. FragmentStore- a comprehensive database of fragments linking metabolites, toxic molecules and drugs Nucleic Acids Res, 2011, 39(suppl-1), D1049-D1054.
[38]
Lagunin, A.; Stepanchikova, A.; Filimonov, D.; Poroikov, V. PASS: Prediction of activity spectra for biologically active substances. Bioinformatics, 2000, 16(8), 747-748.
[http://dx.doi.org/10.1093/bioinformatics/16.8.747] [PMID: 11099264]
[39]
Desai, N.C.; Shukla, H.K.; Tahker, K.A. Some new 2-aryl-3-isonicotamido-4-thiazolidinones and their 5-carboxymethyl homologues as potential antitubercular and antibacterial agents. J. Indian Chem. Soc., 1984, 61, 239-240.
[40]
Monga, V.; Goyal, K.; Steindel, M.; Malhotra, M.; Rajani, D.P.; Rajani, S.D. Synthesis and evaluation of new chalcones, derived pyrazoline and cyclohexenone derivatives as potent antimicrobial, antitubercular and antileishmanial agents. Med. Chem. Res., 2014, 23, 2019-2032.
[http://dx.doi.org/10.1007/s00044-013-0803-1]
[41]
Lipinski, C.A. Lead- and drug-like compounds: the rule-of-five revolution. Drug Discov. Today. Technol., 2004, 1(4), 337-341.
[http://dx.doi.org/10.1016/j.ddtec.2004.11.007] [PMID: 24981612]
[42]
Veber, D.F.; Johnson, S.R.; Cheng, H-Y.; Smith, B.R.; Ward, K.W.; Kopple, K.D. Molecular properties that influence the oral bioavailability of drug candidates. J. Med. Chem., 2002, 45(12), 2615-2623.
[http://dx.doi.org/10.1021/jm020017n] [PMID: 12036371]
[43]
Borges, A.; Abreu, A.C.; Dias, C.; Saavedra, M.J.; Borges, F.; Simões, M. New perspectives on the use of phytochemicals as an emergent strategy to control bacterial infections including biofilms. Molecules, 2016, 21(7), 877.
[http://dx.doi.org/10.3390/molecules21070877] [PMID: 27399652]
[44]
Vento, S.; Lanzafame, M. Tuberculosis and cancer: a complex and dangerous liaison. Lancet Oncol., 2011, 12(6), 520-522.
[http://dx.doi.org/10.1016/S1470-2045(11)70105-X] [PMID: 21624773]
[45]
Zhou, Y.; Hu, Z.; Cao, S.; Yan, B.; Qian, J.; Zhong, H. Concomitant Mycobacterium tuberculosis infection promotes lung tumor growth through enhancing Treg development. Oncol. Rep., 2017, 38(2), 685-692.
[http://dx.doi.org/10.3892/or.2017.5733] [PMID: 28627635]
[46]
Tripoli, E.; LaGuardia, M.; Giammanco, S.; Di-Majo, D.; Giammanco, M. Citrus flavonoids: Molecular structure, biological activity and nutritional properties: A review. Food Chem., 2007, 104(2), 466-479.
[http://dx.doi.org/10.1016/j.foodchem.2006.11.054]
[47]
Damtoft, S.; Jensen, S.R. Three phenylethanoid glucosides of unusual structure from Chirita sinensis (Gesneriaceae). Phytochemistry, 1994, 37(2), 441-443.
[http://dx.doi.org/10.1016/0031-9422(94)85075-5] [PMID: 7765624]
[48]
Swarnalatha, S.; Umamaheswari, A.; Puratchikody, A. Immunomodulatory activity of kaempferol 5-O-b-Dglucopyranoside from IndigoferaaspalathoidesVahl ex DC (Papilionaceae). Med. Chem. Res., 2015, 24(7), 2889-2897.
[http://dx.doi.org/10.1007/s00044-015-1341-9]
[49]
Revised National TB Control Programme Training Manual for Mycobacterium tuberculosis Culture & Drug susceptibility testing; Ministry of Health and Family Welfare: India, 2009.
[50]
Tostmann, A.; Boeree, M.J.; Aarnoutse, R.E.; de Lange, W.C.M.; van der Ven, A.J.A.M.; Dekhuijzen, R. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review. J. Gastroenterol. Hepatol., 2008, 23(2), 192-202.
[http://dx.doi.org/10.1111/j.1440-1746.2007.05207.x] [PMID: 17995946]
[51]
Hassan, H.M.; Guo, H.; Yousef, B.A.; Ping-Ping, D.; Zhang, L.; Jiang, Z. Dexamethasone pre-treatment alleviates isoniazid/lipopolysaccharide hepatotoxicity: Inhibition of inflammatory and oxidative stress. Front. Pharmacol., 2017, 8, 133.
[http://dx.doi.org/10.3389/fphar.2017.00133] [PMID: 28360859]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy