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This study aimed to identify and characterize repurposed drugs that simultaneously target parasite-encoded and host-associated mechanisms essential for VL pathogenesis. Methods: Two complementary in silico drug repurposing strategies were employed. The first method utilized electron\u2013ion interaction potential (EIIP) screening followed by molecular docking and molecular dynamics (MD) simulations targeting two L. donovani proteins: Rab5a and pteridine reductase 1 (PTR1). The second approach employed network-based drug repurposing using the Drugst.One platform, prioritizing candidates via STAT3-associated gene networks. Predicted drug\u2013target complexes were validated by 100 ns MD simulations, and pharmacokinetic parameters were assessed via ADMET profiling using QikProp v7.0 and SwissADME web server. Results: Entecavir and valganciclovir showed strong binding to Rab5a and PTR1, respectively, with Glide Scores of \u22129.36 and \u22129.10 kcal\/mol, and corresponding MM-GBSA \u0394G_bind values of \u221214.00 and \u221213.25 kcal\/mol, confirming their stable interactions and repurposing potential. Network-based analysis identified nifuroxazide as the top candidate targeting the host JAK2\/TYK2\u2013STAT3 axis, with high stability confirmed in MD simulations. Nifuroxazide also displayed the most favorable ADMET profile, including oral bioavailability, membrane permeability, and absence of PAINS alerts. Conclusions: This study highlights the potential of guanine analogs such as entecavir and valganciclovir, and the nitrofuran derivative nifuroxazide, as promising multi-target drug repurposing candidates for VL. Their mechanisms support a dual strategy targeting both parasite biology and host immunoregulation, warranting further preclinical investigation.<\/jats:p>","DOI":"10.3390\/pharmaceutics17081021","type":"journal-article","created":{"date-parts":[[2025,8,6]],"date-time":"2025-08-06T15:09:53Z","timestamp":1754492993000},"page":"1021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Drug Repurposing for Kala-Azar"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1248-5864","authenticated-orcid":false,"given":"Biljana","family":"Arsi\u0107","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Sciences and Mathematics, University of Ni\u0161, Vi\u0161egradska 33, 18000 Ni\u0161, Serbia"},{"name":"Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22607 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2808-3501","authenticated-orcid":false,"given":"Budimir S.","family":"Ili\u0107","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Medicine, University of Ni\u0161, Blvd. Dr Zorana \u0110in\u0111i\u0107a 81, 18000 Ni\u0161, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4408-0068","authenticated-orcid":false,"given":"Andreas","family":"Maier","sequence":"additional","affiliation":[{"name":"Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22607 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3992-0125","authenticated-orcid":false,"given":"Michael","family":"Hartung","sequence":"additional","affiliation":[{"name":"Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22607 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jovana","family":"Janji\u0107","sequence":"additional","affiliation":[{"name":"Faculty of Biology, University of Belgrade, Studentski trg 16, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7783-6218","authenticated-orcid":false,"given":"Jelena","family":"Mili\u0107evi\u0107","sequence":"additional","affiliation":[{"name":"Laboratory for Bioinformatics and Computational Chemistry, Institute of Nuclear Sciences \u201cVin\u010da\u201d, University of Belgrade, Mike Petrovi\u0107a Alasa 12-14, 11000 Belgrade, Serbia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Baumbach","sequence":"additional","affiliation":[{"name":"Institute for Computational Systems Biology, University of Hamburg, Albert-Einstein-Ring 8-10, 22607 Hamburg, Germany"},{"name":"Computational Biomedicine Lab, Department of Mathematics and Computer Science, University of Southern Denmark, 5230 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,6]]},"reference":[{"key":"ref_1","unstructured":"WHO (2024, July 18). Leishmaniasis. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/leishmaniasis."},{"key":"ref_2","first-page":"2049936120966449","article-title":"Overcoming the global burden of neglected tropical diseases","volume":"7","year":"2020","journal-title":"Ther. Adv. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Cec\u00edlio, P., Cordeiro-da-Silva, A., and Oliveira, F. (2022). Sand flies: Basic information on the vectors of leishmaniasis and their interactions with Leishmania parasites. Commun. Biol., 5.","DOI":"10.1038\/s42003-022-03240-z"},{"key":"ref_4","unstructured":"CDC (2024, July 18). Leishmanisasis, Available online: https:\/\/www.cdc.gov\/leishmaniasis\/about\/?CDC_AAref_Val=https:\/\/www.cdc.gov\/parasites\/leishmaniasis\/index.html."},{"key":"ref_5","unstructured":"ECDC (2025, August 03). Phlebotomine Sand Flies\u2014Factsheet for Experts. Available online: https:\/\/www.ecdc.europa.eu\/en\/disease-vectors\/facts\/phlebotomine-sand-flies."},{"key":"ref_6","unstructured":"Garcia, H.H., Tanowitz, H.B., and Del Brutto, O.H. (2013). Chapter 13: Neurological manifestations of human leishmaniasis. Handbook of Clinical Neurology (3rd Series) Neuroparasitology and Tropical Neurology, Elsevier."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"149","DOI":"10.4269\/ajtmh.1995.52.149","article-title":"Neurologic changes in visceral leishmaniasis","volume":"52","author":"Hashim","year":"1995","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Krishnamurthy, N., Grimshaw, A.A., Axson, S.A., Choe, S.H., and Miller, J.E. (2022). Drug repurposing: A systematic review on root causes, barriers and facilitators. BMC Health Serv. Res., 22.","DOI":"10.1186\/s12913-022-08272-z"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1038\/nrd1468","article-title":"Drug repositioning: Identifying and developing new uses for existing drugs","volume":"3","author":"Ashburn","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_10","first-page":"51","article-title":"Drug repositioning: A review","volume":"4","author":"Deotarse","year":"2015","journal-title":"Int. J. Pharm. Sci. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s11095-013-1170-9","article-title":"Computational models for neglected diseases: Gaps and opportunities","volume":"31","author":"Ponder","year":"2014","journal-title":"Pharm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1093\/jac\/dku069","article-title":"Activity of anti-cancer protein kinase inhibitors against Leishmania spp.","volume":"69","author":"Sanderson","year":"2014","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1007\/s10156-004-0348-9","article-title":"Challenges and new discoveries in the treatment of leishmaniasis","volume":"10","author":"Singh","year":"2004","journal-title":"J. Infect. Chemother."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"967","DOI":"10.2741\/4629","article-title":"Leishmaniasis treatment: Update of possibilities for drug repurposing","volume":"23","author":"Martins","year":"2018","journal-title":"Front. Biosci Landmrk"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Veljkovic, V., Glisic, S., Perovic, V., Veljkovic, M., and Paessler, S. (2022). Simple theoretical criterion for selection of natural compounds with anti-COVID-19 activity. Front. Biosci., 27.","DOI":"10.31083\/j.fbl2705152"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Arsic, B., Barber, J., Cikos, A., Kadirvel, M., Kostic, E., McBain, A.J., Milicevic, J., Oates, A., and Regan, A. (2022). Computational studies on selected macrolides active against Escherichia coli combined with the NMR study of tylosin A in deuterated chloroform. Molecules, 27.","DOI":"10.3390\/molecules27217280"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"W481","DOI":"10.1093\/nar\/gkae388","article-title":"Drugst.One-a plug-and-play solution for online systems medicine and network-based drug repurposing","volume":"52","author":"Maier","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S0167-6296(02)00126-1","article-title":"The price of innovation: New estimates of drug development costs","volume":"22","author":"DiMasi","year":"2003","journal-title":"J. Health Econ."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1103\/PhysRevLett.29.105","article-title":"Simple general-model pseudopotential","volume":"29","author":"Veljkovic","year":"1972","journal-title":"Phys. Rev. Lett."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Petrovi\u0107, S., Arsi\u0107, B., Zlatanovi\u0107, I., Mili\u0107evi\u0107, J., Gli\u0161i\u0107, S., Miti\u0107, M., \u0110urovi\u0107-Pej\u010dev, R., and Stojanovi\u0107, G. (2023). In silico investigation of selected pesticides and their determination in agricultural products using QuEChERS methodology and HPLC-DAD. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24098003"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"441","DOI":"10.2174\/092986707779941014","article-title":"Application of the EIIP\/ISM bioinformatics concept in development of new drugs","volume":"14","author":"Veljkovic","year":"2007","journal-title":"Curr. Med. Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2324","DOI":"10.1021\/acs.jcim.5b00559","article-title":"ZINC 15\u2013Ligand discovery for everyone","volume":"55","author":"Sterling","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_23","first-page":"544","article-title":"Crystal structure of the GDP-bound GTPase domain of Rab5a from Leishmania donovani","volume":"F76","author":"Zohib","year":"2020","journal-title":"Acta Cryst."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.pep.2004.08.015","article-title":"Overexpression in Escherichia coli and purification of pteridine reductase (Ptr1) from a clinical isolate of Leishmania donovani","volume":"38","author":"Kumar","year":"2004","journal-title":"Protein Expr. Purif."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"W174","DOI":"10.1093\/nar\/gkv342","article-title":"I-TASSER server: New development for protein structure and function predictions","volume":"43","author":"Yang","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1742","DOI":"10.1093\/jac\/dkq189","article-title":"Molecular docking, structure\u2013activity relationship and biological evaluation of the anticancer drug monastrol as a pteridine reductase inhibitor in a clinical isolate of Leishmania donovani","volume":"65","author":"Kaur","year":"2010","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_27","first-page":"D845","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Ronzano","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Levi, H., Elkon, R., and Shamir, R. (2021). DOMINO: A network-based active module identification algorithm with reduced rate of false calls. Mol. Syst. Biol., 17.","DOI":"10.15252\/msb.20209593"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1093\/bioinformatics\/btac067","article-title":"The DOMINO web-server for active module identification analysis","volume":"38","author":"Levi","year":"2022","journal-title":"Bioinformatics"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1093\/nar\/30.1.303","article-title":"DIP, the Database of Interacting Proteins: A research tool for studying cellular networks of protein interactions","volume":"30","author":"Xenarios","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41586-020-2188-x","article-title":"A reference map of the human binary protein interactome","volume":"580","author":"Luck","year":"2020","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"D362","DOI":"10.1093\/nar\/gkw937","article-title":"The STRING database in 2017: Quality-controlled protein\u2013protein association networks, made broadly accessible","volume":"45","author":"Szklarczyk","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1016\/j.cels.2018.03.001","article-title":"Systematic evaluation of molecular networks for discovery of disease genes","volume":"6","author":"Huang","year":"2018","journal-title":"Cell Syst."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A software environment for integrated models of biomolecular interaction networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3518","DOI":"10.1038\/s41467-020-17189-2","article-title":"Exploring the SARS-CoV-2 virus-host-drug interactome for drug repurposing","volume":"11","author":"Sadegh","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"W98","DOI":"10.1093\/nar\/gkw373","article-title":"KeyPathwayMinerWeb: Online multi-omics network enrichment","volume":"44","author":"List","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1021\/acs.jmedchem.1c01765","article-title":"Investigation of janus kinase (JAK) inhibitors for lung delivery and the importance of aldehyde oxidase metabolism","volume":"65","author":"Wellaway","year":"2022","journal-title":"J. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"14335","DOI":"10.1021\/acs.jmedchem.3c01373","article-title":"Targeting the tyrosine kinase 2 (TYK2) pseudokinase domain: Discovery of the selective TYK2 inhibitor ABBV-712","volume":"66","author":"Breinlinger","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2514","DOI":"10.1021\/acs.jcim.7b00412","article-title":"Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations: A cross-docking study","volume":"57","author":"Liu","year":"2017","journal-title":"J. Chem. Inf. Model."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Daina, A., Michielin, O., and Zoete, V. (2017). SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci. Rep., 7.","DOI":"10.1038\/srep42717"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1016\/j.febslet.2007.01.090","article-title":"Rab cascades and tethering factors in the endomembrane system","volume":"581","author":"Markgraf","year":"2007","journal-title":"FEBS Lett."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"14732","DOI":"10.1074\/jbc.M116.716514","article-title":"Rab5 isoforms specifically regulate different modes of endocytosis in Leishmania","volume":"291","author":"Rastogi","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1126\/science.286.5441.971","article-title":"Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen","volume":"286","author":"Mayer","year":"1999","journal-title":"Science"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1021\/jm030644s","article-title":"Glide: A new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening","volume":"47","author":"Halgren","year":"2004","journal-title":"J. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1021\/jm051256o","article-title":"Extra precision Glide:\u2009 docking and scoring incorporating a model of hydrophobic enclosure for protein\u2212ligand complexes","volume":"49","author":"Friesner","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1007\/s10822-012-9575-9","article-title":"Docking performance of the glide program as evaluated on the Astex and DUD datasets: A complete set of glide SP results and selected results for a new scoring function integrating WaterMap and glide","volume":"26","author":"Repasky","year":"2012","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"402","DOI":"10.3350\/cmh.2021.0179","article-title":"Entecavir versus tenofovir in patients with chronic hepatitis B: Enemies or partners in the prevention of hepatocellular carcinoma","volume":"27","author":"Lee","year":"2021","journal-title":"Clin. Mol. Hepatol."},{"key":"ref_48","first-page":"33","article-title":"Structure of recombinant Leishmania donovani pteridine reductase reveals a disordered active site","volume":"F67","author":"Barrack","year":"2011","journal-title":"Acta Cryst."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5.8.1","DOI":"10.1002\/0471250953.bi0508s52","article-title":"Protein structure and function prediction using I-TASSER","volume":"52","author":"Yang","year":"2015","journal-title":"Curr. Protoc. Bioinform."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"W407","DOI":"10.1093\/nar\/gkm290","article-title":"ProSA-web: Interactive web service for the recognition of errors in three-dimensional structures of proteins","volume":"35","author":"Wiederstein","year":"2007","journal-title":"Nucleic Acids Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with AlphaFold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1126\/science.abj8754","article-title":"Accurate prediction of protein structures and interactions using a three-track neural network","volume":"373","author":"Baek","year":"2021","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.clinthera.2018.07.006","article-title":"Antiviral therapies for herpesviruses: Current agents and new directions","volume":"40","author":"Poole","year":"2018","journal-title":"Clin. Ther."},{"key":"ref_54","first-page":"1","article-title":"Classical and modern drug treatments for leishmaniasis, Topics in Medicinal Chemistry","volume":"Volume 39","author":"Vermelho","year":"2022","journal-title":"Antiprotozoal Drug Development and Delivery"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"992","DOI":"10.1002\/eji.201040940","article-title":"Expression of IL-10-triggered STAT3-dependent IL-4R\u03b1 is required for induction of arginase 1 in visceral leishmaniasis","volume":"41","author":"Biswas","year":"2011","journal-title":"Eur. J. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"175776","DOI":"10.1016\/j.ejphar.2023.175776","article-title":"Pharmacological updates of nifuroxazide: Promising preclinical effects and the underlying molecular mechanisms","volume":"951","author":"Althagafy","year":"2023","journal-title":"Eur. J. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"6724","DOI":"10.1016\/j.bmc.2008.05.076","article-title":"Antileishmanial activity screening of 5-nitro-2-heterocyclic benzylidene hydrazides","volume":"16","author":"Rando","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5095","DOI":"10.1182\/blood-2007-12-129718","article-title":"Nifuroxazide inhibits survival of multiple myeloma cells by directly inhibiting STAT3","volume":"112","author":"Nelson","year":"2008","journal-title":"Blood"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"e1701","DOI":"10.1038\/cddis.2015.63","article-title":"Nifuroxazide induces apoptosis and impairs pulmonary metastasis in breast cancer model","volume":"6","author":"Yang","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Ye, T., Yu, X., Lei, Q., Yang, F., Xia, Y., Song, X., Liu, L., Deng, H., and Gao, T. (2016). Nifuroxazide exerts potent anti-tumor and anti-metastasis activity in melanoma. Sci. Rep., 6.","DOI":"10.1038\/srep20253"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e2534","DOI":"10.1038\/cddis.2016.452","article-title":"Inhibition of Stat3 signaling pathway by nifuroxazide improves antitumor immunity and impairs colorectal carcinoma metastasis","volume":"8","author":"Ye","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Samant, M., Sahu, U., Pandey, S.C., and Khare, P. (2021). Role of cytokines in experimental and human visceral leishmaniasis. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.624009"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Heppler, L.N., Attarha, S., Persaud, R., Brown, J.I., Wang, P., Petrova, B., To\u0161i\u0107, I., Burton, F.B., Flamand, Y., and Walker, S.R. (2022). The antimicrobial drug pyrimethamine inhibits STAT3 transcriptional activity by targeting the enzyme dihydrofolate reductase. J. Biol Chem., 298.","DOI":"10.1016\/j.jbc.2021.101531"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1021\/ml100146z","article-title":"Identification of niclosamide as a new small-molecule inhibitor of the STAT3 signaling pathway","volume":"1","author":"Ren","year":"2010","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1080\/14756366.2016.1260564","article-title":"Probing the druggability of membrane-bound Rab5 by molecular dynamics simulations","volume":"32","author":"Edler","year":"2017","journal-title":"J. Enzyme Inhib. Med. Chem."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Verma, J.K., Rastogi, R., and Mukhopadhyay, A. (2017). Leishmania donovani resides in modified early endosomes by upregulating Rab5a expression via the downregulation of miR-494. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006459"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3936","DOI":"10.1016\/j.csbj.2020.11.033","article-title":"Structure-based discovery of neoandrographolide as a novel inhibitor of Rab5 to suppress cancer growth","volume":"18","author":"Zhang","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1158\/0008-5472.CAN-18-2192","article-title":"Disruption of endolysosomal RAB5\/7 efficiently eliminates colorectal cancer stem cells","volume":"79","author":"Takeda","year":"2019","journal-title":"Cancer Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1107\/S2053230X22002795","article-title":"Crystal structure of the ternary complex of Leishmania major pteridine reductase 1 with the cofactor NADP+\/NADPH and the substrate folic acid","volume":"78","author":"Mangani","year":"2022","journal-title":"Acta Crystallogr. F Struct. Biol. Commun."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/88584","article-title":"Pteridine reductase mechanism correlates pterin metabolism with drug resistance in trypanosomatid parasites","volume":"8","author":"Gourley","year":"2001","journal-title":"Nat. Struct. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Arthur, M.N., Hanson, G., Broni, E., Sakyi, P.O., Mensah-Brown, H., Miller, W.A., and Kwofie, S.K. (2025). Natural product identification and molecular docking studies of Leishmania major pteridine reductase inhibitors. Pharmaceuticals, 18.","DOI":"10.3390\/ph18010006"},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Di Pisa, F., Landi, G., Dello Iacono, L., Pozzi, C., Borsari, C., Ferrari, S., Santucci, M., Santarem, N., Cordeiro-da-Silva, A., and Moraes, C.B. (2017). Chroman-4-one derivatives targeting pteridine reductase 1 and showing anti-parasitic activity. Molecules, 22.","DOI":"10.3390\/molecules22030426"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1128\/AAC.31.3.447","article-title":"Biological activity of analogs of guanine and guanosine against American Trypanosoma and Leishmania spp.","volume":"31","author":"Avila","year":"1987","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1073\/pnas.80.1.288","article-title":"Metabolism and mechanism of action of formycin B in Leishmania","volume":"80","author":"Rainey","year":"1983","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Intakhan, N., Saeung, A., Rodrigues Oliveira, S.M., Pereira, M.L., and Chanmol, W. (2024). Synergistic effects of artesunate in combination with amphotericin B and miltefosine against Leishmania infantum: Potential for dose reduction and enhanced therapeutic strategies. Antibiotics, 13.","DOI":"10.3390\/antibiotics13090806"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.1016\/S1473-3099(23)00353-5","article-title":"The status of combination therapy for visceral leishmaniasis: An updated review","volume":"24","author":"Dorlo","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.cbpa.2006.03.004","article-title":"Mode of action of natural and synthetic drugs against Trypanosoma cruzi and their interaction with the mammalian host","volume":"146","author":"Maya","year":"2007","journal-title":"Comp. Biochem. Physiol. A"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"2012","DOI":"10.1039\/D3MD00220A","article-title":"Design, synthesis, electrochemistry and anti-trypanosomatid hit\/lead identification of nitrofuranylazines","volume":"14","author":"Saayman","year":"2023","journal-title":"RSC Med. Chem."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1021\/acs.jcim.2c01589","article-title":"Selectivity and ranking of tight-binding JAK-STAT inhibitors using Markovian milestoning with Voronoi tessellations","volume":"63","author":"Ojha","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1182\/blood-2005-06-2413","article-title":"The structural basis of janus kinase 2 inhibition by a potent and specific pan-janus kinase inhibitor","volume":"107","author":"Lucet","year":"2006","journal-title":"Blood"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"105092","DOI":"10.1016\/j.ejps.2019.105092","article-title":"An update on derivatisation and repurposing of clinical nitrofuran drugs","volume":"140","author":"Zuma","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"8973","DOI":"10.1021\/acs.jmedchem.9b00444","article-title":"Highly selective inhibition of tyrosine kinase 2 (TYK2) for the treatment of autoimmune diseases: Discovery of the allosteric inhibitor BMS-986165","volume":"62","author":"Wrobleski","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1007\/s00044-023-03035-9","article-title":"The pyridazine heterocycle in molecular recognition and drug discovery","volume":"32","author":"Meanwell","year":"2023","journal-title":"Med. Chem Res."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"8953","DOI":"10.1021\/acs.jmedchem.9b00443","article-title":"Identification of N-methyl nicotinamide and N-methyl pyridazine-3-carboxamide pseudokinase domain ligands as highly selective allosteric inhibitors of tyrosine kinase 2 (TYK2)","volume":"62","author":"Moslin","year":"2019","journal-title":"J. Med. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Li, X., Shen, R., Wang, X., Zhang, F., Liu, S., Li, D., Liu, J., Li, P., and Yan, Y. (2022). Novel small molecule tyrosine kinase 2 pseudokinase ligands block cytokine-induced TYK2-mediated signaling pathways. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.884399"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/s41392-021-00791-1","article-title":"The JAK\/STAT signaling pathway: From bench to clinic","volume":"6","author":"Hu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1208\/s12248-014-9670-z","article-title":"Lipid-based drug carriers for prodrugs to enhance drug delivery","volume":"17","author":"Zaro","year":"2015","journal-title":"AAPS J."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Jung, H.J., Ho, M.J., Ahn, S., Han, Y.T., and Kang, M.J. (2018). Synthesis and physicochemical evaluation of entecavir-fatty acid conjugates in reducing food effect on intestinal absorption. Molecules, 23.","DOI":"10.3390\/molecules23040731"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"2719","DOI":"10.1021\/jm901137j","article-title":"New substructure filters for removal of pan assay interference compounds (PAINS) from screening libraries and for their exclusion in bioassays","volume":"53","author":"Baell","year":"2010","journal-title":"J. Med. Chem."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.2174\/15680266113139990033","article-title":"In silico ADMET prediction: Recent advances, current challenges and future trends","volume":"13","author":"Cheng","year":"2013","journal-title":"Curr. Top. Med. Chem."}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/8\/1021\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:24:54Z","timestamp":1760034294000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/17\/8\/1021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,6]]},"references-count":90,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["pharmaceutics17081021"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics17081021","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,6]]}}}