Abstract
Background and Introduction: Tuberculosis (TB) is a leading infectious disease caused by Mycobacterium tuberculosiswith high morbidity and mortality. Isocitrate lyase (MtbICL), a key enzyme of glyoxylate pathway has been shown to be involved in mycobacterial persistence, is attractive drug target against persistent tuberculosis.
Methods: Virtual screening, molecular docking and MD simulation study has been integrated for screening of phytochemical based anti-mycobacterial compounds. Docking study of reported MtbICL inhibitors has shown an average binding affinity score -7.30 Kcal/mol. In virtual screening, compounds exhibiting lower binding energy than calculated average binding energy were selected as top hit compounds followed by calculation of drug likeness property. Relationship between experimental IC50 value and calculated binding gibbs free energy of reported inhibitors was also calculated through regression analysis to predict IC50 value of potential inhibitors.
Results: Docking and MD simulation studies of top hit compounds have identified shinjudilactone (quassinoid), lecheronol A (pimarane) and caniojane (diterpene) as potential MtbICL inhibitors.
Conclusion: Phytochemical based anti-mycobacterial compound can further developed into effective drugs against persistence tuberculosis with lesser toxicity and side effects.
Keywords: Tuberculosis, Isocitrate lyase, Mycobacterial persistence, Molecular docking, MD simulation, Virtual screening.
Graphical Abstract
[1]
Koch, R. Classics in infectious diseases. The etiology of tuberculosis: Robert Koch. Berlin, Germany 1882. Rev. Infect. Dis., 1982, 4(6), 1270-1274. [http://dx.doi.org/10.1093/clinids/4.6.1270]. [PMID: 6818657].
[2]
WHO. Global tuberculosis report 2017 2018 , http://www. who.int/tb/publications/global_report/en/ [Accessed Apr 9];
[3]
Bennett, J.E.; Dolin, R.; Blaser, M.J. Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases E-Book; Elsevier Health Sciences, 2014.
[4]
Smith, I. Mycobacterium tuberculosis pathogenesis and molecular determinants of virulence. Clin. Microbiol. Rev., 2003, 16(3), 463-496. [http://dx.doi.org/10.1128/CMR.16.3.463-496.2003]. [PMID: 12857778].
[5]
Koul, A.; Arnoult, E.; Lounis, N.; Guillemont, J.; Andries, K. The challenge of new drug discovery for tuberculosis. Nature, 2011, 469(7331), 483-490. [http://dx.doi.org/10.1038/nature09657]. [PMID: 21270886].
[6]
Kahlon, A.; Sharma, A. Computational systems biology perspective on tuberculosis in big data era: Challenges and future goals. In: Big Data Analytics in Bioinformatics and Healthcare; IGI GLOBAL, 2015; pp. 240-264.
[7]
McKinney, J.D.; Höner zu Bentrup, K.; Muñoz-Elías, E.J.; Miczak, A.; Chen, B.; Chan, W-T.; Swenson, D.; Sacchettini, J.C.; Jacobs, W.R., Jr; Russell, D.G. Persistence of Mycobacterium tuberculosis in macrophages and mice requires the glyoxylate shunt enzyme isocitrate lyase. Nature, 2000, 406(6797), 735-738. [http://dx.doi.org/10.1038/35021074]. [PMID: 10963599].
[8]
Lorenz, M.C.; Fink, G.R. The glyoxylate cycle is required for fungal virulence. Nature, 2001, 412(6842), 83-86. [http://dx.doi.org/10.1038/35083594]. [PMID: 11452311].
[9]
Muñoz-Elías, E.J.; McKinney, J.D.M. Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence. Nat. Med., 2005, 11(6), 638-644. [http://dx.doi.org/ 10.1038/nm1252]. [PMID: 15895072].
[10]
Sharma, V.; Sharma, S.; Hoener zu Bentrup, K.; McKinney, J.D.; Russell, D.G.; Jacobs, W.R., Jr; Sacchettini, J.C. Structure of isocitrate lyase, a persistence factor of Mycobacterium tuberculosis. Nat. Struct. Biol., 2000, 7(8), 663-668. [http://dx.doi.org/ 10.1038/77964]. [PMID: 10932251].
[11]
Lohman Jeremy, R.; Olson Andrew, C.; Remington, S. James. Atomic Resolution Structures of Escherichia Coli and Bacillus Anthracis Malate Synthase A: Comparison with isoform G and implications for structure‐based drug discovery. Protein Sci., 2009, 17, 1935-1945. [http://dx.doi.org/10.1110/ps.036269.108].
[12]
Moynihan, M.M.; Murkin, A.S. Cysteine is the general base that serves in catalysis by isocitrate lyase and in mechanism-based inhibition by 3-nitropropionate. Biochemistry, 2014, 53(1), 178-187. [http://dx.doi.org/10.1021/bi401432t]. [PMID: 24354272].
[13]
Jongkon, N.; Chotpatiwetchkul, W.; Gleeson, M.P. Probing the catalytic mechanism involved in the isocitrate lyase superfamily: Hybrid quantum mechanical/molecular mechanical calculations on 2,3-Dimethylmalate Lyase. J. Phys. Chem. B, 2015, 119(35), 11473-11484. [http://dx.doi.org/10.1021/acs.jpcb.5b04732]. [PMID: 26224328].
[14]
Shukla, H.; Kumar, V.; Singh, A.K.; Rastogi, S.; Khan, S.R.; Siddiqi, M.I.; Krishnan, M.Y.; Akhtar, M.S. Isocitrate lyase of Mycobacterium tuberculosis is inhibited by quercetin through binding at N-terminus. Int. J. Biol. Macromol., 2015, 78, 137-141. [http://dx.doi.org/10.1016/j.ijbiomac.2015.04.005]. [PMID: 25869309].
[15]
Casenghi, M.; Cole, S.T.; Nathan, C.F. New approaches to filling the gap in tuberculosis drug discovery. PLoS Med., 2007, 4(11)e293 [http://dx.doi.org/10.1371/journal.pmed.0040293]. [PMID: 17988169].
[16]
Butler, M.S. Natural products to drugs: natural product-derived compounds in clinical trials. Nat. Prod. Rep., 2008, 25(3), 475-516. [http://dx.doi.org/10.1039/b514294f]. [PMID: 18497896].
[17]
García, A.; Bocanegra-García, V.; Palma-Nicolás, J.P.; Rivera, G. Recent advances in antitubercular natural products. Eur. J. Med. Chem., 2012, 49, 1-23. [http://dx.doi.org/10.1016/ j.ejmech.2011.12.029]. [PMID: 22280816].
[18]
Sansinenea, E.; Ortiz, A. Antitubercular natural terpenoids: Recent developments and syntheses. Curr. Org. Synth., 2014, 11, 545-591. [http://dx.doi.org/10.2174/1570179411666140321180629].
[19]
Berman, H.M.; Westbrook, J.; Feng, Z.; Gilliland, G.; Bhat, T.N.; Weissig, H.; Shindyalov, I.N.; Bourne, P.E. The Protein Data Bank, 1999-. In: International Tables for Crystallography Volume F: Crystallography of biological macromolecules;; Rossmann, M.G.; Arnold, E., Eds.; Springer Netherlands: Dordrecht,, 2001; pp. 675-684.
[20]
Morris Garrett, M. sing AutoDock for ligandreceptor docking. Curr. Protoc. Bioinforma., 2008, 24 8.14.1-8.14.40.
[21]
Pettersen, E.F.; Goddard, T.D.; Huang, C.C.; Couch, G.S.; Greenblatt, D.M.; Meng, E.C.; Ferrin, T.E. UCSF Chimera--A visualization system for exploratory research and analysis. J. Comput. Chem., 2004, 25(13), 1605-1612. [http://dx.doi.org/10.1002/ jcc.20084]. [PMID: 15264254].
[22]
Sharma, A.; Dutta, P.; Sharma, M.; Rajput, N.K.; Dodiya, B.; Georrge, J.J.; Kholia, T.; Bhardwaj, A. BioPhytMol: A drug discovery community resource on anti-mycobacterial phytomolecules and plant extracts. J. Cheminform., 2014, 6(1), 46. [http://dx.doi.org/10.1186/s13321-014-0046-2]. [PMID: 25360160].
and plant extracts. J. Cheminform., 2014, 6(1) [http://dx.doi.org/10.1186/s13321-014-0046-2.[PMID: 25360160] .
and plant extracts. J. Cheminform., 2014, 6(1) [http://dx.doi.org/10.1186/s13321-014-0046-2.[PMID: 25360160] .
[23]
Wang, Y.; Xiao, J.; Suzek, T.O.; Zhang, J.; Wang, J.; Bryant, S.H. PubChem: A public information system for analyzing bioactivities of small molecules. Nucleic Acids Res., 2009, 37(Web Server issue), W623-33. [http://dx.doi.org/10.1093/nar/gkp456. [PMID: 19498078] .
[24]
Kim, S.; Thiessen, P.A.; Bolton, E.E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B.A.; Wang, J.; Yu, B.; Zhang, J.; Bryant, S.H. PubChem substance and compound databases. Nucleic Acids Res., 2016, 44(D1), D1202-D1213. [http://dx.doi.org/10.1093/nar/gkv951]. [PMID: 26400175].
[25]
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, 33. [http://dx.doi.org/10.1186/1758-2946-3-33]. [PMID: 21982300].
[26]
Ihlenfeldt, W.D.; Bolton, E.E.; Bryant, S.H. The PubChem chemical structure sketcher. J. Cheminform., 2009, 1(1), 20. [http://dx.doi.org/10.1186/1758-2946-1-20]. [PMID: 20298522].
[27]
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].
[28]
Dallakyan, S.; Olson, A.J. Small-molecule library screening by docking with PyRx. Methods Mol. Biol., 2015, 1263, 243-250. [http://dx.doi.org/10.1007/978-1-4939-2269-7_19]. [PMID: 25618350].
[29]
Guex, N.; Peitsch, M.C. SWISS-MODEL and the Swiss-PdbViewer: An environment for comparative protein modeling. Electrophoresis, 1997, 18(15), 2714-2723. [http://dx.doi.org/ 10.1002/elps.1150181505]. [PMID: 9504803].
[30]
Drug Likeness Tool. (Accessed at. http://www.niper.gov.in/pi_dev_ tools/DruLiToWeb/DruLiTo_index.html (Accessed on April 11, 2018).
[31]
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].
[32]
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].
[33]
Wallace, A.C.; Laskowski, R.A.; Thornton, J.M. LIGPLOT: A program to generate schematic diagrams of protein-ligand interactions. Protein Eng., 1995, 8(2), 127-134. [http://dx.doi.org/ 10.1093/protein/8.2.127]. [PMID: 7630882].
[34]
Adcock, S.A.; McCammon, J.A. Molecular dynamics: Survey of methods for simulating the activity of proteins. Chem. Rev., 2006, 106(5), 1589-1615. [http://dx.doi.org/10.1021/cr040426m]. [PMID: 16683746].
[35]
Abraham, M.J.; Murtola, T.; Schulz, R.; Páll, S.; Smith, J.C.; Hess, B.; Lindahl, E. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 2015, 1-2, 19-25. [http://dx.doi.org/10.1016/ j.softx.2015.06.001].
[36]
Kumari, R.; Kumar, R.; Lynn, A. g_mmpbsa--A GROMACS tool for high-throughput MM-PBSA calculations. J. Chem. Inf. Model., 2014, 54(7), 1951-1962. [http://dx.doi.org/10.1021/ci500020m]. [PMID: 24850022].
[37]
Schloss, J.V.; Cleland, W.W. Inhibition of isocitrate lyase by 3-nitropropionate, a reaction-intermediate analogue. Biochemistry, 1982, 21(18), 4420-4427. [http://dx.doi.org/10.1021/bi00261a035]. [PMID: 7126549].
[38]
Ko, Y.H.; McFadden, B.A. Alkylation of isocitrate lyase from Escherichia coli by 3-bromopyruvate. Arch. Biochem. Biophys., 1990, 278(2), 373-380. [http://dx.doi.org/10.1016/0003-9861(90)90273-2]. [PMID: 2183722].
[39]
McFadden, B.A.; Purohit, S. Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera. J. Bacteriol., 1977, 131(1), 136-144. [PMID: 17593].
[40]
Krátký, M.; Vinšová, J. Advances in mycobacterial isocitrate lyase targeting and inhibitors. Curr. Med. Chem., 2012, 19(36), 6126-6137. [http://dx.doi.org/10.2174/0929867311209066126]. [PMID: 23092127].
[41]
Shingnapurkar, D.; Dandawate, P.; Anson, C.E.; Powell, A.K.; Afrasiabi, Z.; Sinn, E.; Pandit, S.; Venkateswara Swamy, K.; Franzblau, S.; Padhye, S. Synthesis and characterization of pyruvate-isoniazid analogs and their copper complexes as potential ICL inhibitors. Bioorg. Med. Chem. Lett., 2012, 22(9), 3172-3176. [http://dx.doi.org/10.1016/j.bmcl.2012.03.047]. [PMID: 22475559].
[42]
Sriram, D.; Yogeeswari, P.; Methuku, S.; Vyas, D.R.K.; Senthilkumar, P.; Alvala, M.; Jeankumar, V.U. Synthesis of various 3-nitropropionamides as Mycobacterium tuberculosis isocitrate lyase inhibitor. Bioorg. Med. Chem. Lett., 2011, 21(18), 5149-5154. [http://dx.doi.org/10.1016/j.bmcl.2011.07.062]. [PMID: 21840711].
[43]
Sriram, D.; Yogeeswari, P.; Senthilkumar, P.; Dewakar, S.; Rohit, N.; Debjani, B.; Bhat, P.; Veugopal, B.; Pavan, V.V.S.; Thimmappa, H.M. Novel phthalazinyl derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis isocitrate lyase enzyme. Med. Chem., 2009, 5(5), 422-433. [http://dx.doi.org/10.2174/157340609789117886]. [PMID: 19534678].
[44]
Sriram, D.; Yogeeswari, P.; Senthilkumar, P.; Sangaraju, D.; Nelli, R.; Banerjee, D.; Bhat, P.; Manjashetty, T.H. Synthesis and antimycobacterial evaluation of novel Phthalazin-4-ylacetamides against log- and starved phase cultures. Chem. Biol. Drug Des., 2010, 75(4), 381-391. [http://dx.doi.org/10.1111/j.1747-0285.2010.00947.x]. [PMID: 20148903].
[45]
Sriram, D.; Yogeeswari, P.; Vyas, D.R.K.; Senthilkumar, P.; Bhat, P.; Srividya, M. 5-Nitro-2-furoic acid hydrazones: Design, synthesis and in vitro antimycobacterial evaluation against log and starved phase cultures. Bioorg. Med. Chem. Lett., 2010, 20(15), 4313-4316. [http://dx.doi.org/10.1016/j.bmcl.2010.06.096]. [PMID: 20615698].
[46]
Sriram, D.; Yogeeswari, P.; Senthilkumar, P.; Naidu, G.; Bhat, P. 5-Nitro-2,6-dioxohexahydro-4-pyrimidinecarboxamides: Synthesis, in vitro antimycobacterial activity, cytotoxicity, and isocitrate lyase inhibition studies. J. Enzyme Inhib. Med. Chem., 2010, 25(6), 765-772. [http://dx.doi.org/10.3109/14756360903425221]. [PMID: 20569083].
[47]
Banerjee, D.; Yogeeswari, P.; Bhat, P.; Thomas, A.; Srividya, M.; Sriram, D. Novel isatinyl thiosemicarbazones derivatives as potential molecule to combat HIV-TB co-infection. Eur. J. Med. Chem., 2011, 46(1), 106-121. [http://dx.doi.org/10.1016/j.ejmech. 2010.10.020]. [PMID: 21093117].
[48]
Lu, J.; Yue, J.; Wu, J.; Luo, R.; Hu, Z.; Li, J.; Bai, Y.; Tang, Z.; Xian, Q.; Zhang, X.; Wang, H. In vitro and in vivo activities of a new lead compound I2906 against Mycobacterium tuberculosis. Pharmacology, 2010, 85(6), 365-371. [http://dx.doi.org/10.1159/ 000299795]. [PMID: 20530976].
[49]
Ji, L.; Long, Q.; Yang, D.; Xie, J. Identification of mannich base as a novel inhibitor of Mycobacterium tuberculosis isocitrate by high-throughput screening. Int. J. Biol. Sci., 2011, 7(3), 376-382. [http://dx.doi.org/10.7150/ijbs.7.376]. [PMID: 21494431].
[50]
Kozic, J.; Novotná, E.; Volková, M.; Stolaříková, J.; Trejtnar, F.; Wsól, V.; Vinšová, J. Synthesis and in vitro antimycobacterial and isocitrate lyase inhibition properties of novel 2-methoxy-2′-hydroxybenzanilides, their thioxo analogues and benzoxazoles. Eur. J. Med. Chem., 2012, 56, 108-119. [http://dx.doi.org/10.1016/ j.ejmech.2012.08.016]. [PMID: 22960697].
[51]
Krátký, M.; Vinšová, J.; Novotná, E.; Mandíková, J.; Wsól, V.; Trejtnar, F.; Ulmann, V.; Stolaříková, J.; Fernandes, S.; Bhat, S.; Liu, J.O. Salicylanilide derivatives block Mycobacterium tuberculosis through inhibition of isocitrate lyase and methionine aminopeptidase. Tuberculosis (Edinb.), 2012, 92(5), 434-439. [http://dx.doi.org/10.1016/j.tube.2012.06.001]. [PMID: 22765970].
[52]
Langer, T.; Hoffmann, R.D. Virtual screening: An effective tool for lead structure discovery? Curr. Pharm. Des., 2001, 7(7), 509-527. [http://dx.doi.org/10.2174/1381612013397861]. [PMID: 11375766].
[53]
Gautam, R.; Saklani, A.; Jachak, S.M. Indian medicinal plants as a source of antimycobacterial agents. J. Ethnopharmacol., 2007, 110(2), 200-234. [http://dx.doi.org/10.1016/j.jep.2006.12.031]. [PMID: 17276637].
[54]
Shen, L.; Maddox, M.M.; Adhikari, S.; Bruhn, D.F.; Kumar, M.; Lee, R.E.; Hurdle, J.G.; Lee, R.E.; Sun, D. Syntheses and evaluation of macrocyclic engelhardione analogs as antitubercular and antibacterial agents. J. Antibiot. (Tokyo), 2013, 66(6), 319-325. [http://dx.doi.org/10.1038/ja.2013.21]. [PMID: 23549356].
Call for Papers in Thematic Issues
30 September, 2024
Medicinal Chemistry Advancement in Life-Threatening Diseases
The current issue will highlight concise reports that specify ground-breaking insights, including the novel discovery of drug targets and their action mechanism or drugs of novel classes. These are projected to encourage medicinal chemistry future efforts to address the most challenging medical needs. The current issue highlights further efforts to ...read more
Related Journals
Current Medicinal Chemistry
Current Pharmaceutical Design
Current Respiratory Medicine Reviews
Medicinal Chemistry
Infectious Disorders - Drug Targets
Mini-Reviews in Medicinal Chemistry
Endocrine, Metabolic & Immune Disorders - Drug Targets
Anti-Infective Agents
Coronaviruses
Recent Advances in Inflammation & Allergy Drug Discovery
Related Books
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Frontiers in Natural Product Chemistry
Therapeutic Use of Plant Secondary Metabolites
Therapeutic Implications of Natural Bioactive Compounds
Frontiers in Bioactive Compounds
Mitochondrial DNA and the Immuno-inflammatory Response: New Frontiers to Control Specific Microbial Diseases
Frontiers in Natural Product Chemistry
Frontiers in Clinical Drug Research – Anti Allergy Agents
Frontiers in Natural Product Chemistry
Science of Spices and Culinary Herbs - Latest Laboratory, Pre-clinical, and Clinical Studies
Article Metrics
43
4