Login Register Cart 0
Generic placeholder image

Infectious Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5265
ISSN (Online): 2212-3989

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

Targeting Trypanothione Reductase of Leishmanial major to Fight Against Cutaneous Leishmaniasis

Author(s): Abdul Aziz A. Bin Dukhyil*

Volume 19, Issue 4, 2019

Page: [388 - 393] Pages: 6

DOI: 10.2174/1871526518666180502141849

Price: $65

Abstract

Background: 1.2-2.0 million cases of leishmaniasis occur annually throughout the world. The available drugs like Amphotericin B, antimonials and miltefosine are unable to fulfill the need due to less effectiveness, high toxicity, resistance, high cost and complex route of administration. Leishmania survives inside the macrophages through different evasion mechanisms; one of that is activation of its trypanothione reductase enzyme which neutralizes the reactive oxygen species generated inside the macrophages to kill the parasites. This enzyme is unique and absent in human, therefore in this study I targeted it for screening of new inhibitors to fight against leishmaniasis.

Methods: Homology modeling of Leishmania major trypanothione reductase was performed using Phyre2 server. The homology based modelled protein was validated with PROCHECK analysis. Ligplot analysis was performed to predict the active residues inside the binding pocket. Further, virtual screening of ligand library containing 113 ligands from PubChem Bioassay was performed against the target using AutoDock Vina Tool.

Results: Top five ligands showed best binding affinity. The molecule having PubChem CID: 10553746 showed highest binding affinity of -11.3 kcal/mol. Over all this molecule showed highest binding affinity and moderate number of hydrogen bonds. Hopefully, this molecule will be able to block the activity of target enzyme, trypanothione reductase of Leishmania major effectively and may work as new molecules to fight against cutaneous leishmanaisis.

Conclusion: This study will help the researchers to identify the new molecules which can block the activity of leishmanial-trypanothione reductase, a novel enzyme of trypanosomatids. These screened inhibitors may also be effective not only in leishmaniasis but also other trypanosomatid-mediated infectious diseases.

Keywords: Leishmania major, trypanothione reductase, homology modeling, virtual screening, macrophages, leishmaniasi, cutaneous.

Graphical Abstract

[1]
Duarte, M.C.; Lage, D.P.; Martins, V.T.; Chávez-Fumagalli, M.A.; Roatt, B.M.; Menezes-Souza, D.; Goulart, L.R.; Soto, M.; Tavares, C.A.; Coelho, E.A. Recent updates and perspectives on approaches for the development of vaccines against visceral leishmaniasis. Rev. Soc. Bras. Med. Trop., 2016, 49(4), 398-407.
[http://dx.doi.org/10.1590/0037-8682-0120-2016] [PMID: 27598624]
[2]
Vannier-Santos, M.A.; Martiny, A.; de Souza, W. Cell biology of Leishmania spp.: invading and evading. Curr. Pharm. Des., 2002, 8(4), 297-318.
[http://dx.doi.org/10.2174/1381612023396230] [PMID: 11860368]
[3]
Rub, A.; Dey, R.; Jadhav, M.; Kamat, R.; Chakkaramakkil, S.; Majumdar, S.; Mukhopadhyaya, R.; Saha, B. Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function. Nat. Immunol., 2009, 10(3), 273-280.
[http://dx.doi.org/10.1038/ni.1705] [PMID: 19198591]
[4]
Rub, A.; Arish, M.; Husain, S.A.; Ahmed, N.; Akhter, Y. Host-lipidome as a potential target of protozoan parasites. Microbes Infect., 2013, 15(10-11), 649-660.
[http://dx.doi.org/10.1016/j.micinf.2013.06.006] [PMID: 23811020]
[5]
Arish, M.; Husein, A.; Kashif, M.; Sandhu, P.; Hasnain, S.E.; Akhter, Y.; Rub, A. Orchestration of membrane receptor signaling by membrane lipids. Biochimie, 2015, 113, 111-124.
[http://dx.doi.org/10.1016/j.biochi.2015.04.005] [PMID: 25890158]
[6]
Torres-Guerrero, E.; Quintanilla-Cedillo, M.R.; Ruiz-Esmenjaud, J.; Arenas, R. Leishmaniasis: a review. F1000 Res., 2017, 6, 750.
[http://dx.doi.org/10.12688/f1000research.11120.1] [PMID: 28649370]
[7]
Kashif, M.; Tabrez, S.; Husein, A.; Arish, M.; Kalaiarasan, P.; Manna, P.P.; Subbarao, N.; Akhter, Y.; Rub, A. Identification of novel inhibitors against UDP-galactopyranose mutase to combat leishmaniasis. J. Cell. Biochem., 2017.
[http://dx.doi.org/10.1002/jcb.26433] [PMID: 29058760]
[8]
Sundar, S.; Jha, T.K.; Thakur, C.P.; Bhattacharya, S.K.; Rai, M. Oral miltefosine for the treatment of Indian visceral leishmaniasis. Trans. R. Soc. Trop. Med. Hyg., 2006, 100(Suppl. 1), S26-S33.
[http://dx.doi.org/10.1016/j.trstmh.2006.02.011] [PMID: 16730038]
[9]
Moore, E.M.; Lockwood, D.N. Treatment of visceral leishmaniasis. J. Glob. Infect. Dis., 2010, 2(2), 151-158.
[http://dx.doi.org/10.4103/0974-777X.62883] [PMID: 20606971]
[10]
Jerônimo, S.M.; Pearson, R.D. The challenges on developing vaccine against visceral leishmaniasis. Rev. Soc. Bras. Med. Trop., 2016, 49(4), 395-397.
[http://dx.doi.org/10.1590/0037-8682-0343-2016] [PMID: 27598623]
[11]
Harms, G.; Scherbaum, H.; Reiter-Owona, I.; Stich, A.; Richter, J. Treatment of imported New World cutaneous leishmaniasis in Germany. Int. J. Dermatol., 2011, 50(11), 1336-1342.
[http://dx.doi.org/10.1111/j.1365-4632.2011.04987.x] [PMID: 22004484]
[12]
Ilari, A.; Fiorillo, A.; Genovese, I.; Colotti, G. Polyamine-trypanothione pathway: an update. Future Med. Chem., 2017, 9(1), 61-77.
[http://dx.doi.org/10.4155/fmc-2016-0180] [PMID: 27957878]
[13]
Ilari, A.; Fiorillo, A.; Baiocco, P.; Poser, E.; Angiulli, G.; Colotti, G. Targeting polyamine metabolism for finding new drugs against leishmaniasis: a review. Mini Rev. Med. Chem., 2015, 15(3), 243-252.
[http://dx.doi.org/10.2174/138955751503150312141044] [PMID: 25769972]
[14]
Kelley, L.A.; Mezulis, S.; Yates, C.M.; Wass, M.N.; Sternberg, M.J. The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protoc., 2015, 10(6), 845-858.
[http://dx.doi.org/10.1038/nprot.2015.053] [PMID: 25950237]
[15]
Laskowski, R.A.; Rullmannn, J.A.; MacArthur, M.W.; Kaptein, R.; Thornton, J.M. AQUA and PROCHECK-NMR: programs for checking the quality of protein structures solved by NMR. J. Biomol. NMR, 1996, 8(4), 477-486.
[http://dx.doi.org/10.1007/BF00228148] [PMID: 9008363]
[16]
Kashif, M.; Manna, P.P.; Akhter, Y.; Alaidarous, M.; Rub, A. Screening of Novel Inhibitors Against Leishmania donovani Calcium ion Channel to Fight Leishmaniasis. Infect. Disord. Drug Targets, 2017, 17(2), 120-129.
[http://dx.doi.org/10.2174/1871526516666161230124513] [PMID: 28034363]
[17]
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]
[18]
Lill, M.A.; Danielson, M.L. Computer-aided drug design platform using PyMOL. J. Comput. Aided Mol. Des., 2011, 25(1), 13-19.
[http://dx.doi.org/10.1007/s10822-010-9395-8] [PMID: 21053052]
[19]
Mathur, R.K.; Awasthi, A.; Wadhone, P.; Ramanamurthy, B.; Saha, B. Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nat. Med., 2004, 10(5), 540-544.
[http://dx.doi.org/10.1038/nm1045] [PMID: 15107845]
[20]
Awasthi, A.; Mathur, R.; Khan, A.; Joshi, B.N.; Jain, N.; Sawant, S.; Boppana, R.; Mitra, D.; Saha, B. CD40 signaling is impaired in L. major-infected macrophages and is rescued by a p38MAPK activator establishing a host-protective memory T cell response. J. Exp. Med., 2003, 197(8), 1037-1043.
[http://dx.doi.org/10.1084/jem.20022033] [PMID: 12695487]
[21]
Arias, D.G.; Herrera, F.E.; Garay, A.S.; Rodrigues, D.; Forastieri, P.S.; Luna, L.E.; Bürgi, M.D.; Prieto, C.; Iglesias, A.A.; Cravero, R.M.; Guerrero, S.A. Rational design of nitrofuran derivatives: Synthesis and valuation as inhibitors of Trypanosoma cruzi trypanothione reductase. Eur. J. Med. Chem., 2017, 125, 1088-1097.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.055] [PMID: 27810595]

Rights & Permissions Print Cite
Article Metrics
13
3
© 2024 Bentham Science Publishers | Privacy Policy