Login Register Cart 0
Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Virtual Screening of Novel Phytocompound(s) with Potential to Combat Mycobacterium tuberculosis Infection

Author(s): Anchal Aggarwal, Shilpa Sharma and Deepa Khare*

Volume 20, Issue 5, 2023

Published on: 11 August, 2022

Page: [570 - 580] Pages: 11

DOI: 10.2174/1570180819666220523152239

Price: $65

Abstract

Background: Tuberculosis is a worldwide health concern, and there is an immediate need for effective therapeutics to inhibit the infection caused by Mycobacterium tuberculosis. The persistent state of bacteria and the emergence of Multi-Drug Resistance are the two major reasons for the difficulty in treating tuberculosis.

Objective: The study aims to identify novel phytocompounds to effectively inhibit Mycobacterium tuberculosis by targeting the Esx-1 protein, which plays a vital function in the secretion pathway of M. tuberculosis to successfully disrupt the host cell and cause tuberculosis.

Methods: In the current study, ~500 novel phytocompounds were screened by docking against Esx-1 using AutoDock Vina 4.2 version. The visualization analysis for selected phytocompounds was performed using Protein-Ligand Interaction Profiler. A comparative study with a well-known drug for tuberculosis, Rifampicin, was also performed. Moreover, ADMET analysis was performed to check the druggability and pharmacokinetic parameters of the selected compounds.

Results: Based on the analysis, cadabicine, an alkaloid produced by Cadaba fruticose (Vizhuthi), Crataeva nurvala (Varuna) plants, exhibits the best binding affinity of -7.8 Kcal/mol with the active site residues, Leu 29 and Trp 43, of Esx-1, which are required for the stability of Esx-1 and virulence of M. tuberculosis in the host cell. ADMET analysis showed that cadabicine exhibits better druggability and pharmacokinetic parameters than other selected compounds.

Conclusion: Cadabicine possesses an acceptable binding affinity with the active site of Esx-1 and exhibits acceptable physicochemical and pharmacokinetic properties, which makes it a potential new drug candidate for the treatment of tuberculosis.

Keywords: Phytocompounds, Mycobacterium tuberculosis, small molecule inhibitors, Esx-1, type VII secretion system, cadabicine, Auto Dock Vina, ADMET analysis, PLIP, multiple drug resistance, extensive drug resistance.

« Previous Next »
Graphical Abstract

[1]
Bloom, B.R.; Atun, R.; Cohen, T.; Dye, C.; Fraser, H.; Gomez, G.B.; Knight, G.; Murray, M.; Nardell, E.; Rubin, E.; Salomon, J.; Vassall, A.; Volchenkov, G.; White, R.; Wilson, D.; Yadav, P. Tuberculosis. In: Major Infect. Dis, 3rd ed; Holmes, K.K., Ed.; The International Bank for Reconstruction and Development/The World Bank, 2017.
[http://dx.doi.org/10.1596/978-1-4648-0524-0_ch11]
[2]
Dunlap, N.E.; Briles, D.E. Immunology of tuberculosis. Med. Clin. North Am., 1993, 77(6), 1235-1251.
[http://dx.doi.org/10.1016/S0025-7125(16)30190-0] [PMID: 8231409]
[3]
Kumarasamy, N.; Vallabhaneni, S.; Flanigan, T.P.; Mayer, K.H.; Solomon, S. Clinical profile of HIV in India. Indian J. Med. Res., 2005, 121(4), 377-394.
[PMID: 15817951]
[4]
Daniel, T.M. The history of tuberculosis. Respir. Med., 2006, 100(11), 1862-1870.
[http://dx.doi.org/10.1016/j.rmed.2006.08.006] [PMID: 16949809]
[5]
Cole, S.T.; Brosch, R.; Parkhill, J.; Garnier, T.; Churcher, C.; Harris, D.; Gordon, S.V.; Eiglmeier, K.; Gas, S.; Barry, C.E., III; Tekaia, F.; Badcock, K.; Basham, D.; Brown, D.; Chillingworth, T.; Connor, R.; Davies, R.; Devlin, K.; Feltwell, T.; Gentles, S.; Hamlin, N.; Holroyd, S.; Hornsby, T.; Jagels, K.; Krogh, A.; McLean, J.; Moule, S.; Murphy, L.; Oliver, K.; Osborne, J.; Quail, M.A.; Rajandream, M.A.; Rogers, J.; Rutter, S.; Seeger, K.; Skelton, J.; Squares, R.; Squares, S.; Sulston, J.E.; Taylor, K.; Whitehead, S.; Barrell, B.G. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature, 1998, 393(6685), 537-544.
[http://dx.doi.org/10.1038/31159] [PMID: 9634230]
[6]
Garces, A.; Atmakuri, K.; Chase, M.R.; Woodworth, J.S.; Krastins, B.; Rothchild, A.C.; Ramsdell, T.L.; Lopez, M.F.; Behar, S.M.; Sarracino, D.A.; Fortune, S.M. EspA acts as a critical mediator of ESX1-dependent virulence in Mycobacterium tuberculosis by affecting bacterial cell wall integrity. PLoS Pathog., 2010, 6(6), e1000957.
[http://dx.doi.org/10.1371/journal.ppat.1000957] [PMID: 20585630]
[7]
Houben, D.; Demangel, C.; van Ingen, J.; Perez, J.; Baldeón, L.; Abdallah, A.M.; Caleechurn, L.; Bottai, D.; van Zon, M.; de Punder, K.; van der Laan, T.; Kant, A.; Bossers-de Vries, R.; Willemsen, P.; Bitter, W.; van Soolingen, D.; Brosch, R.; van der Wel, N.; Peters, P.J. ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria. Cell. Microbiol., 2012, 14(8), 1287-1298.
[http://dx.doi.org/10.1111/j.1462-5822.2012.01799.x] [PMID: 22524898]
[8]
Xu, J.; Laine, O.; Masciocchi, M.; Manoranjan, J.; Smith, J.; Du, S.J.; Edwards, N.; Zhu, X.; Fenselau, C.; Gao, L.Y. A unique Mycobacterium ESX-1 protein co-secretes with CFP-10/ESAT-6 and is necessary for inhibiting phagosome maturation. Mol. Microbiol., 2007, 66(3), 787-800.
[http://dx.doi.org/10.1111/j.1365-2958.2007.05959.x] [PMID: 17908204]
[9]
Wintola, O.A.; Afolayan, A.J. The antibacterial, phytochemicals and antioxidants evaluation of the root extracts of Hydnora Africana Thunb. used as antidysenteric in Eastern Cape Province, South Africa. BMC Complement. Altern. Med., 2015, 15(1), 307.
[http://dx.doi.org/10.1186/s12906-015-0835-9] [PMID: 26335685]
[10]
da Silva, A.P.S.; Nascimento da Silva, L.C.; Martins da Fonseca, C.S.; de Araújo, J.M.; Correia, M.T.; Cavalcanti, M.S.; Lima, V.L. Antimicrobial activity and phytochemical analysis of organic extracts from Cleome spinosa Jaqc. Front. Microbiol., 2016, 7, 963.
[http://dx.doi.org/10.3389/fmicb.2016.00963] [PMID: 27446005]
[11]
Toda, M.; Okubo, Y.; Ohnishi, R.; Shimamura, T. About the antibacterial and bactericidal action of Japanese tea. Jpn. J. Bacteriol., 1989, 44(4), 669-672.
[http://dx.doi.org/10.3412/jsb.44.669] [PMID: 2677434]
[12]
Borris, R.P. Natural products research: Perspectives from a major pharmaceutical company. J. Ethnopharmacol., 1996, 51(1-3), 29-38.
[http://dx.doi.org/10.1016/0378-8741(95)01347-4] [PMID: 9213624]
[13]
Batista, O.; Duarte, A.; Nascimento, J.; Simões, M.F.; de la Torre, M.C.; Rodríguez, B. Structure and antimicrobial activity of diterpenes from the roots of Plectranthus hereroensis. J. Nat. Prod., 1994, 57(6), 858-861.
[http://dx.doi.org/10.1021/np50108a031] [PMID: 7931371]
[14]
Sakanaka, S.; Shimura, N.; Aizawa, M.; Kim, M.; Yamamoto, T. Preventive effect of green tea polyphenols against dental caries in conventional rats. Biosci. Biotechnol. Biochem., 1992, 56(4), 592-594.
[http://dx.doi.org/10.1271/bbb.56.592] [PMID: 27280653]
[15]
Kazmi, M.H.; Malik, A.; Hameed, S.; Akhtar, N.; Noor Ali, S. An anthraquinone derivative from Cassia italica. Phytochemistry, 1994, 36(3), 761-763.
[http://dx.doi.org/10.1016/S0031-9422(00)89812-X]
[16]
Cowan, M.M. Plant products as antimicrobial agents. Clin. Microbiol. Rev., 1999, 12(4), 564-582.
[http://dx.doi.org/10.1128/CMR.12.4.564] [PMID: 10515903]
[17]
van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: Towards prediction paradise? Nat. Rev. Drug Discov., 2003, 2(3), 192-204.
[http://dx.doi.org/10.1038/nrd1032] [PMID: 12612645]
[18]
Sharma, S.; Gupta, M.; Sharma, A.; Agarwal, S.M. Oral bioavailability of naturally occurring anticancer phytomolecules. Lett. Drug Des. Discov., 2018, 15(11), 1180-1188.
[http://dx.doi.org/10.2174/1570180815666180109161014]
[19]
Daina, A.; Michielin, O.; Zoete, V. SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 2017, 7(1), 42717.
[http://dx.doi.org/10.1038/srep42717] [PMID: 28256516]
[20]
Bottai, D.; Frigui, W.; Clark, S.; Rayner, E.; Zelmer, A.; Andreu, N.; de Jonge, M.I.; Bancroft, G.J.; Williams, A.; Brodin, P.; Brosch, R. Increased protective efficacy of recombinant BCG strains expressing virulence-neutral proteins of the ESX-1 secretion system. Vaccine, 2015, 33(23), 2710-2718.
[http://dx.doi.org/10.1016/j.vaccine.2015.03.083] [PMID: 25869896]
[21]
Brodin, P.; de Jonge, M.I.; Majlessi, L.; Leclerc, C.; Nilges, M.; Cole, S.T.; Brosch, R. Functional analysis of early secreted antigenic target-6, the dominant T-cell antigen of Mycobacterium tuberculosis, reveals key residues involved in secretion, complex formation, virulence, and immunogenicity. J. Biol. Chem., 2005, 280(40), 33953-33959.
[http://dx.doi.org/10.1074/jbc.M503515200] [PMID: 16048998]
[22]
Mohanraj, K.; Karthikeyan, B.S.; Vivek-Ananth, R.P.; Chand, R.P.B.; Aparna, S.R.; Mangalapandi, P.; Samal, A. IMPPAT: A curated database of Indian medicinal plants, phytochemistry and therapeutics. Sci. Rep., 2018, 8(1), 4329.
[http://dx.doi.org/10.1038/s41598-018-22631-z] [PMID: 29531263]
[23]
Fatima, S.; Gupta, P.; Sharma, S.; Sharma, A.; Agarwal, S.M. ADMET profiling of geographically diverse phytochemical using chemoinformatic tools. Future Med. Chem., 2020, 12(1), 69-87.
[http://dx.doi.org/10.4155/fmc-2019-0206] [PMID: 31793338]
[24]
Korotkova, N.; Piton, J.; Wagner, J.M.; Boy-Röttger, S.; Japaridze, A.; Evans, T.J.; Cole, S.T.; Pojer, F.; Korotkov, K.V. Structure of EspB, a secreted substrate of the ESX-1 secretion system of Mycobacterium tuberculosis. J. Struct. Biol., 2015, 191(2), 236-244.
[http://dx.doi.org/10.1016/j.jsb.2015.06.003] [PMID: 26051906]
[25]
McLaughlin, B.; Chon, J.S.; MacGurn, J.A. A mycobacterium ESX-1-secreted virulence factor with unique requirements for export. PLoS Pathog., 2007, 3(8), e105.
[http://dx.doi.org/10.1371/journal.ppat.0030105]
[26]
Houben, E.N.G.; Korotkov, K.V.; Bitter, W. Take five - Type VII secretion systems of Mycobacteria. Biochim. Biophys. Acta, 2014, 1843(8), 1707-1716.
[http://dx.doi.org/10.1016/j.bbamcr.2013.11.003] [PMID: 24263244]
[27]
Zondervan, N.A.; van Dam, J.C.J.; Schaap, P.J.; Martins Dos Santos, V.A.P.; Suarez-Diez, M. Regulation of three virulence strategies of Mycobacterium tuberculosis: A success story. Int. J. Mol. Sci., 2018, 19(2), 347.
[http://dx.doi.org/10.3390/ijms19020347] [PMID: 29364195]
[28]
Steingart, K.R.; Schiller, I.; Horne, D.J.; Pai, M.; Boehme, C.C.; Dendukuri, N. Xpert® MTB/RIF assay for pulmonary tuberculosis and rifampicin resistance in adults. Cochrane Database Syst. Rev., 2014, 18(1), CD009593.
[http://dx.doi.org/10.1002/14651858.CD009593.pub3] [PMID: 24448973]
[29]
Saravanan, P.; Dusthackeer, V.N.A.; Rajmani, R.S.; Mahizhaveni, B.; Nirmal, C.R.; Rajadas, S.E.; Bhardwaj, N.; Ponnuraja, C.; Bhaskar, A.; Hemanthkumar, A.K.; Ramachandran, G.; Tripathy, S.P. Discovery of a highly potent novel rifampicin analog by preparing a hybrid of the precursors of the antibiotic drugs rifampicin and clofazimine. Sci. Rep., 2021, 11(1), 1029.
[http://dx.doi.org/10.1038/s41598-020-80439-2] [PMID: 33441878]
[30]
Lodha, D.; Patel, A.K.; Shekhawat, N.S. A high-frequency in vitro multiplication, micromorphological studies and ex vitro rooting of Cadaba fruticosa (L.) Druce (Bahuguni): A multipurpose endangered medicinal shrub. Physiol. Mol. Biol. Plants, 2015, 21(3), 407-415.
[http://dx.doi.org/10.1007/s12298-015-0310-6] [PMID: 26261405]
[31]
Verma, R.; Devre, K.; Gangrade, T.A. Review on phytochemical, pharmacological, and pharmacognostical profile of Cadaba trifoliate. Research & Reviews: J. Pharm. Phytochem., 2014, 2, 35-39.
[32]
Zhang, H.; Ma, Z.F. Phytochemical and Pharmacological Properties of Capparis spinosa as a Medicinal Plant. Nutrients, 2018, 10(2), 116.
[http://dx.doi.org/10.3390/nu10020116] [PMID: 29364841]
[33]
Mythreyi, R.; Sasikala, E.; Geetha, A.; Madhavan, V. Antibacterial activity of leaves of Cadaba trifoliata (Roxb.). Wt. & Arn. Indian J. Pharm. Sci., 2009, 71(2), 115-116.
[http://dx.doi.org/10.4103/0250-474X.54271] [PMID: 20336203]
[34]
Alzahrani, D.A.; Albokhari, E.J.; Yaradua, S.S.; Abba, A. Comparative analysis of chloroplast genomes of four medicinal capparaceae species: Genome structures, phylogenetic relationships and adaptive evolution. Plants, 2021, 10(6), 1229.
[http://dx.doi.org/10.3390/plants10061229] [PMID: 34204211]
[35]
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]
[36]
Macabeo, A.P.; Krohn, K.; Gehle, D.; Read, R.W.; Brophy, J.J.; Cordell, G.A.; Franzblau, S.G.; Aguinaldo, A.M. Indole alkaloids from the leaves of Philippine Alstonia scholaris. Phytochemistry, 2005, 66(10), 1158-1162.
[http://dx.doi.org/10.1016/j.phytochem.2005.02.018] [PMID: 15924920]
[37]
Asres, K.; Bucar, F.; Edelsbrunner, S.; Kartnig, T.; Höger, G.; Thiel, W. Investigations on antimycobacterial activity of some Ethiopian medicinal plants. Phytother. Res., 2001, 15(4), 323-326.
[http://dx.doi.org/10.1002/ptr.724] [PMID: 11406856]
[38]
Kumar, J.K.; Devi Prasad, A.G.; Chaturvedi, V. Phytochemical screening of five medicinal legumes and their evaluation for in vitro anti-tubercular activity. Ayu, 2014, 35(1), 98-102.
[http://dx.doi.org/10.4103/0974-8520.141952] [PMID: 25364208]
[39]
Kumar, S.; Sahu, P.; Jena, L. An in silico approach to identify potential inhibitors against multiple drug targets of Mycobacterium tuberculosis. Int. J. Mycobacteriol., 2019, 8(3), 252-261.
[http://dx.doi.org/10.4103/ijmy.ijmy_109_19] [PMID: 31512601]

Rights & Permissions Print Cite
Article Metrics
21
3
© 2024 Bentham Science Publishers | Privacy Policy