Molecular Insights into the Interaction of Ursolic Acid and Cucurbitacin from Colocynth with Therapeutic Targets of Mycobacterium tuberculosis

Author(s): Mohammad Ajmal Ali*, Mohammad Abul Farah*, Joongku Lee, Khalid M. Al-Anazi, Fahad M.A. Al-Hemaid

Journal Name: Letters in Drug Design & Discovery

Volume 17 , Issue 10 , 2020


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Abstract:

Aims: Medicinal plants like Citrullus colocynthis are a potential choice to produce helpful novel antimycobacterial drugs. The existence of a range of natural products in the plants, especially Ursolic Acid (UA) and cucurbitacin E 2-0-β-d-glucopyranoside (CEG), with promising antibacterial activity against a variety of bacteria, prompted the need to check its actions against Mycobacterium tuberculosis (Mtb).

Background: Mycobacterium tuberculosis (Mtb), an obligate human pathogen causes tuberculosis and is one of the major causes of death worldwide. A few combinations of drugs are currently accessible for treating TB patients, but these are inadequate to tackle worldwide TB cases.

Objective: The molecular interactions between ursolic acid and cucurbitacin E with the eight potential Mtb target proteins were investigated with the objective of finding drug-like inhibitors.

Methods: Avogadro v.1.2.0 and Openbabel v.2.4.1 were used for creating file formats required for docking analysis. Molecular docking was performed with eight different proteins essential for Mtb metabolism and survival. AutoDock v.4.2 and AutoDock vina v.1.1.2 were used for docking and Gromacs 5.1.4 was used for simulation studies.

Results and Discussion: Among the two ligands used in this research, cucurbitacin E showed a better docking score relative to the drugs presently available for all the target proteins. Rifampicin showed the best binding affinity (among known inhibitors) i.e. -10.8 kcal/mol with C terminal caspase recruitment domain. Moreover, ursolic acid and cucurbitacin E showed uniform binding score (above -7.5 kcal/mol) with all the target proteins, acknowledged its availability as a potential multi-target drug.

Conclusions: Ursolic acid can be useful in the creation of novel, multi-targeted and effective anti- TB medicines since it showed stable structure with FabH.

Keywords: AutoDock, binding affinity, toxicity, hydrophobicity, ursolic acid, cucurbitacin E.

[1]
Turner, R.D.; Bothamley, G.H. Cough and the transmission of tuberculosis. J. Infect. Dis., 2015, 211(9), 1367-1372.
[http://dx.doi.org/10.1093/infdis/jiu625] [PMID: 25387581]
[2]
Muñoz, L.; Stagg, H.R.; Abubakar, I. Diagnosis and management of latent tuberculosis infection. Cold Spring Harb. Perspect. Med., 2015, 5(11)a017830
[http://dx.doi.org/10.1101/cshperspect.a017830] [PMID: 26054858]
[3]
Cadena, J.; Rathinavelu, S.; Lopez-Alvarenga, J.C.; Restrepo, B.I. The re-emerging association between tuberculosis and diabetes: Lessons from past centuries. Tuberculosis (Edinb.), 2019, 116S, S89-S97.
[http://dx.doi.org/10.1016/j.tube.2019.04.015] [PMID: 31085129]
[4]
National Academies of Sciences E. Medicine. Addressing Continuous Threats: HIV/AIDS, Tuberculosis, and Malaria.. Global Health and the Future Role of the United States; ; National Academies Press: US,, 2017.
[5]
Cambau, E.; Drancourt, M. Steps towards the discovery of Mycobacterium tuberculosis by Robert Koch, 1882. Clin. Microbiol. Infect., 2014, 20(3), 196-201.
[http://dx.doi.org/10.1111/1469-0691.12555] [PMID: 24450600]
[6]
Marrakchi, H.; Lanéelle, M.A.; Daffé, M. Mycolic acids: Structures, biosynthesis, and beyond. Chem. Biol., 2014, 21(1), 67-85.
[http://dx.doi.org/10.1016/j.chembiol.2013.11.011] [PMID: 24374164]
[7]
Ahmed, M.M.; Velayati, A.A.; Mohammed, S.H. Epidemiology of multidrug-resistant, extensively drug resistant, and totally drug resistant tuberculosis in Middle East countries. Int. J. Mycobacteriol., 2016, 5(3), 249-256.
[http://dx.doi.org/10.1016/j.ijmyco.2016.08.008] [PMID: 27847005]
[8]
Rattan, A.; Kalia, A.; Ahmad, N. Multidrug-resistant Mycobacterium tuberculosis: Molecular perspectives. Emerg. Infect. Dis., 1998, 4(2), 195-209.
[http://dx.doi.org/10.3201/eid0402.980207] [PMID: 9621190]
[9]
Shukla, R.; Shukla, H.; Sonkar, A.; Pandey, T.; Tripathi, T. Structure-based screening and molecular dynamics simulations offer novel natural compounds as potential inhibitors of Mycobacterium tuberculosis isocitrate lyase. J. Biomol. Struct. Dyn., 2018, 36(8), 2045-2057.
[http://dx.doi.org/10.1080/07391102.2017.1341337] [PMID: 28605994]
[10]
Birch, H.L. Molecular and biochemical characterisation of novel glycosyltransferases in Mycobacterium tuberculosis.. Ph.D. Thesis, University of Birmingham, UK, . 2011.
[11]
Veyron-Churlet, R.; Molle, V.; Taylor, R.C.; Brown, A.K.; Besra, G.S.; Zanella-Cléon, I.; Fütterer, K.; Kremer, L. The Mycobacterium tuberculosis β-ketoacyl-acyl carrier protein synthase III activity is inhibited by phosphorylation on a single threonine residue. J. Biol. Chem., 2009, 284(10), 6414-6424.
[http://dx.doi.org/10.1074/jbc.M806537200] [PMID: 19074144]
[12]
Madigan, C.A.; Martinot, A.J.; Wei, J.R.; Madduri, A.; Cheng, T.Y.; Young, D.C.; Layre, E.; Murry, J.P.; Rubin, E.J.; Moody, D.B. Lipidomic analysis links mycobactin synthase K to iron uptake and virulence in M. tuberculosis. PLoS Pathog., 2015, 11(3)e1004792
[http://dx.doi.org/10.1371/journal.ppat.1004792] [PMID: 25815898]
[13]
Yadav, V.; Panilaitis, B.; Shi, H.; Numuta, K.; Lee, K.; Kaplan, D.L. N-acetylglucosamine 6-phosphate deacetylase (nagA) is required for N-acetyl glucosamine assimilation in Gluconacetobacter xylinus. PLoS One, 2011, 6(6)e18099
[http://dx.doi.org/10.1371/journal.pone.0018099] [PMID: 21655093]
[14]
Jensen, D.; Manzano, A.R.; Rammohan, J.; Stallings, C.L.; Galburt, E.A. CarD and RbpA modify the kinetics of initial transcription and slow promoter escape of the Mycobacterium tuberculosis RNA polymerase. Nucleic Acids Res., 2019, 47(13), 6685-6698.
[http://dx.doi.org/10.1093/nar/gkz449] [PMID: 31127308]
[15]
Mushtaq, S.; Abbasi, B.H.; Uzair, B.; Abbasi, R. Natural products as reservoirs of novel therapeutic agents. EXCLI J., 2018, 17, 420-451.
[PMID: 29805348]
[16]
Al-Snafi, A.E. Chemical constituents and pharmacological effects of Cynodon dactylon-A review. IOSR J. Pharm., 2016, 6(7), 17-31.
[http://dx.doi.org/10.9790/3013-06721731]
[17]
Gupta, V.K.; Kumar, M.M.; Bisht, D.; Kaushik, A. Plants in our combating strategies against Mycobacterium tuberculosis: Progress made and obstacles met. Pharm. Biol., 2017, 55(1), 1536-1544.
[http://dx.doi.org/10.1080/13880209.2017.1309440] [PMID: 28385088]
[18]
Jesus, J.A.; Lago, J.H.; Laurenti, M.D.; Yamamoto, E.S.; Passero, L.F. Antimicrobial activity of oleanolic and ursolic acids: An update. Evid. Based Complement. Alternat. Med., 2015.2015620472
[http://dx.doi.org/10.1155/2015/620472] [PMID: 25793002]
[19]
Jyoti, M.A.; Nam, K.W.; Jang, W.S.; Kim, Y.H.; Kim, S.K.; Lee, B.E.; Song, H.Y. Antimycobacterial activity of methanolic plant extract of Artemisia capillaris containing ursolic acid and hydroquinone against Mycobacterium tuberculosis. J. Infect. Chemother., 2016, 22(4), 200-208.
[http://dx.doi.org/10.1016/j.jiac.2015.11.014] [PMID: 26867795]
[20]
López-García, S.; Castañeda-Sanchez, J.I.; Jiménez-Arellanes, A.; Domínguez-López, L.; Castro-Mussot, M.E.; Hernández-Sanchéz, J.; Luna-Herrera, J. Macrophage activation by ursolic and oleanolic acids during mycobacterial infection. Molecules, 2015, 20(8), 14348-14364.
[http://dx.doi.org/10.3390/molecules200814348] [PMID: 26287131]
[21]
Podder, B.; Jang, W.S.; Nam, K.W.; Lee, B.E.; Song, H.Y. Ursolic acid activates intracellular killing effect of macrophages during Mycobacterium tuberculosis infection. J. Microbiol. Biotechnol., 2015, 25(5), 738-744.
[http://dx.doi.org/10.4014/jmb.1407.07020] [PMID: 25406534]
[22]
Mehta, A.; Srivastva, G.; Kachhwaha, S.; Sharma, M.; Kothari, S.L. Antimycobacterial activity of Citrullus colocynthis (L.) Schrad. against drug sensitive and drug resistant Mycobacterium tuberculosis and MOTT clinical isolates. J. Ethnopharmacol., 2013, 149(1), 195-200.
[http://dx.doi.org/10.1016/j.jep.2013.06.022] [PMID: 23816500]
[23]
Dushenkov, V.; Raskin, I. New strategy for the search of natural biologically active substances. Rus. Russ. J. Plant Physiol., 2008, 55(4), 564-567.
[http://dx.doi.org/10.1134/S1021443708040201] [PMID: 19578478]
[24]
Bhusal, R.P.; Bashiri, G.; Kwai, B.X.C.; Sperry, J.; Leung, I.K.H. Targeting isocitrate lyase for the treatment of latent tuberculosis. Drug Discov. Today, 2017, 22(7), 1008-1016.
[http://dx.doi.org/10.1016/j.drudis.2017.04.012] [PMID: 28458043]
[25]
Manina, G.; Pasca, M.R.; Buroni, S.; De Rossi, E.; Riccardi, G. Decaprenylphosphoryl-β-D-ribose 2′-epimerase from Mycobacterium tuberculosis is a magic drug target. Curr. Med. Chem., 2010, 17(27), 3099-3108.
[http://dx.doi.org/10.2174/092986710791959693] [PMID: 20629622]
[26]
Sachdeva, S.; Reynolds, K.A. Mycobacterium tuberculosis β-Ketoacyl acyl carrier Protein synthase III (mtFabH) assay: Principles and Method. New Antibiotic Targets; Springer, 2008, pp. 205-213.
[http://dx.doi.org/10.1007/978-1-59745-246-5_16]
[27]
Ma, Y.; Stern, R.J.; Scherman, M.S.; Vissa, V.D.; Yan, W.; Jones, V.C.; Zhang, F.; Franzblau, S.G.; Lewis, W.H.; McNeil, M.R. Drug targeting Mycobacterium tuberculosis cell wall synthesis: Genetics of dTDP-rhamnose synthetic enzymes and development of a microtiter plate-based screen for inhibitors of conversion of dTDP-glucose to dTDP-rhamnose. Antimicrob. Agents Chemother., 2001, 45(5), 1407-1416.
[http://dx.doi.org/10.1128/AAC.45.5.1407-1416.2001] [PMID: 11302803]
[28]
Davies, J.S.; Coombes, D.; Horne, C.R.; Pearce, F.G.; Friemann, R.; North, R.A.; Dobson, R.C.J. Functional and solution structure studies of amino sugar deacetylase and deaminase enzymes from Staphylococcus aureus. FEBS Lett., 2019, 593(1), 52-66.
[http://dx.doi.org/10.1002/1873-3468.13289] [PMID: 30411345]
[29]
Preiss, L.; Langer, J.D.; Yildiz, Ö.; Eckhardt-Strelau, L.; Guillemont, J.E.; Koul, A.; Meier, T. Structure of the mycobacterial ATP synthase Fo rotor ring in complex with the anti-TB drug bedaquiline. Sci. Adv., 2015, 1(4)e1500106
[http://dx.doi.org/10.1126/sciadv.1500106] [PMID: 26601184]
[30]
Wawrocki, S.; Druszczynska, M. Inflammasomes in Mycobacterium tuberculosis-driven immunity. Can. J. Infect. Dis. Med. Microbiol., 2017, •••20172309478
[http://dx.doi.org/10.1155/2017/2309478] [PMID: 29348763]
[31]
Banerjee, P.; Eckert, A.O.; Schrey, A.K.; Preissner, R. ProTox-II: A webserver for the prediction of toxicity of chemicals. Nucleic Acids Res., 2018, 46(W1), W257-W263.
[http://dx.doi.org/10.1093/nar/gky318] [PMID: 29718510]
[32]
Hanwell, M.D.; Curtis, D.E.; Lonie, D.C.; Vandermeersch, T.; Zurek, E.; Hutchison, G.R. Avogadro: An advanced semantic chemical editor, visualization, and analysis platform. J. Cheminform., 2012, 4(1), 17.
[http://dx.doi.org/10.1186/1758-2946-4-17] [PMID: 22889332]
[33]
O’Boyle, N.M.; Banck, M.; James, C.A.; Morley, C.; Vandermeersch, T.; Hutchison, G.R. Open Babel: An open chemical toolbox. J. Cheminform., 2011, 3(1), 33.
[http://dx.doi.org/10.1186/1758-2946-3-33] [PMID: 21982300]
[34]
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]
[35]
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]
[36]
Hess, B.; Kutzner, C.; van der Spoel, D.; Lindahl, E. Van Der Spoel, D; Lindahl, E. GROMACS 4: Algorithms for highly efficient, load-balanced, and scalable molecular simulation. J. Chem. Theory Comput., 2008, 4(3), 435-447.
[http://dx.doi.org/10.1021/ct700301q] [PMID: 26620784]
[37]
Gurung, A.B.; Bhattacharjee, A.; Ali, M.A. Exploring the physicochemical profile and the binding patterns of selected novel anticancer Himalayan plant derived active compounds with macromolecular targets. Inform. Med. Unlocked, 2016, 5, 1-14.
[http://dx.doi.org/10.1016/j.imu.2016.09.004]
[38]
Seijger, C.; Hoefsloot, W.; Bergsma-de Guchteneire, I.; Te Brake, L.; van Ingen, J.; Kuipers, S.; van Crevel, R.; Aarnoutse, R.; Boeree, M.; Magis-Escurra, C. High-dose rifampicin in tuberculosis: Experiences from a Dutch tuberculosis centre. PLoS One, 2019, 14(3)e0213718
[http://dx.doi.org/10.1371/journal.pone.0213718] [PMID: 30870476]
[39]
LoBue, P.A.; Moser, K.S. Use of isoniazid for latent tuberculosis infection in a public health clinic. Am. J. Respir. Crit. Care Med., 2003, 168(4), 443-447.
[http://dx.doi.org/10.1164/rccm.200303-390OC] [PMID: 12746255]
[40]
den Hertog, A.L.; Menting, S.; Pfeltz, R.; Warns, M.; Siddiqi, S.H.; Anthony, R.M. Pyrazinamide is active against Mycobacterium tuberculosis cultures at neutral pH and low temperature. Antimicrob. Agents Chemother., 2016, 60(8), 4956-4960.
[http://dx.doi.org/10.1128/AAC.00654-16] [PMID: 27270287]
[41]
Murray, J.F.; Schraufnagel, D.E.; Hopewell, P.C. Treatment of tuberculosis. A historical perspective. Ann. Am. Thorac. Soc., 2015, 12(12), 1749-1759.
[http://dx.doi.org/10.1513/AnnalsATS.201509-632PS] [PMID: 26653188]
[42]
Saxena, A.K.; Singh, A. Mycobacterial tuberculosis enzyme targets and their inhibitors. Curr. Top. Med. Chem., 2019, 19(5), 337-355.
[http://dx.doi.org/10.2174/1568026619666190219105722] [PMID: 30806318]
[43]
Brecik, M.; Centárová, I.; Mukherjee, R.; Kolly, G.S.; Huszár, S.; Bobovská, A.; Kilacsková, E.; Mokošová, V.; Svetlíková, Z.; Šarkan, M.; Neres, J.; Korduláková, J.; Cole, S.T.; Mikušová, K. DprE1 is a vulnerable tuberculosis drug target due to its cell wall localization. ACS Chem. Biol., 2015, 10(7), 1631-1636.
[http://dx.doi.org/10.1021/acschembio.5b00237] [PMID: 25906160]
[44]
Kurczab, R.; Śliwa, P.; Rataj, K.; Kafel, R.; Bojarski, A.J. Salt bridge in ligand-protein complexes-systematic theoretical and statistical investigations. J. Chem. Inf. Model., 2018, 58(11), 2224-2238.
[http://dx.doi.org/10.1021/acs.jcim.8b00266] [PMID: 30351056]
[45]
Scarsdale, J.N.; Kazanina, G.; He, X.; Reynolds, K.A.; Wright, H.T. Crystal structure of the Mycobacterium tuberculosis beta-ketoacyl-acyl carrier protein synthase III. J. Biol. Chem., 2001, 276(23), 20516-20522.
[http://dx.doi.org/10.1074/jbc.M010762200] [PMID: 11278743]
[46]
Laurie, A.T.; Jackson, R.M. Q-SiteFinder: An energy-based method for the prediction of protein-ligand binding sites. Bioinformatics, 2005, 21(9), 1908-1916.
[http://dx.doi.org/10.1093/bioinformatics/bti315] [PMID: 15701681]


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VOLUME: 17
ISSUE: 10
Year: 2020
Published on: 11 October, 2020
Page: [1309 - 1318]
Pages: 10
DOI: 10.2174/1570180817999200514102750
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