{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:08:05Z","timestamp":1785434885881,"version":"3.56.0"},"reference-count":71,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red","award":["CB 2021"],"award-info":[{"award-number":["CB 2021"]}]},{"award":["CB 2021"],"award-info":[{"award-number":["CB 2021"]}],"id":[{"id":"https:\/\/ror.org\/02g87qh62","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/00ca2c886","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004837","name":"Ministerio de Ciencia e Innovaci\u00f3n","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004837","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/05r0vyz12","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Uni\u00f3n Europea\u2013NextGenerationEU"},{"id":[{"id":"https:\/\/ror.org\/037x4qk98","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002809","name":"Generalitat de Catalunya","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002809","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/01bg62x04","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003030","name":"Generalitat of Catalonia Universities and Research Department","doi-asserted-by":"publisher","award":["2021 SGR 01562"],"award-info":[{"award-number":["2021 SGR 01562"]}],"id":[{"id":"10.13039\/501100003030","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Chagas disease, caused by the parasite Trypanosoma cruzi, remains a major neglected tropical disease, with millions of people living with the infection worldwide. Current treatments are effective in the acute stage of the disease, but are poorly tolerated and show reduced efficacy in chronic infections, highlighting an urgent need for novel therapeutic strategies. A key bottleneck in early-stage drug discovery is target identification, which is traditionally dependent on costly and low-throughput experimental methods. Computational approaches offer a cost-effective and fast alternative to traditional methods. Methods: In this study, we present an integrated in silico pipeline that combines ligand-based and structure-based computational approaches to prioritize potential molecular targets for bioactive compounds against T. cruzi. The ligand-based component performed similarity searches across curated bioactivity databases containing known ligand\u2013protein associations, and the most similar candidates were then further evaluated using a structure-based approach through pairwise structural alignment against the T. cruzi proteome from AlphaFold. Results: The pipeline was validated using eight compounds with known targets, successfully recovering the correct target in six cases. Additionally, two compounds with anti-T. cruzi activity but unknown mechanisms of action were analyzed to hypothesize their potential targets. Conclusions: Overall, the pipeline demonstrated moderate success, with limitations arising from challenges in handling novel chemotypes and poorly annotated targets. Nevertheless, its modular nature allows for an easy adaptation to other neglected tropical diseases, providing a flexible and cost-effective framework for early-stage target prioritization.<\/jats:p>","DOI":"10.3390\/ph19071046","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T13:19:31Z","timestamp":1783430371000},"page":"1046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating Molecular Similarity and AlphaFold-Based Structural Alignment for Target Discovery in Trypanosoma cruzi"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1003-5376","authenticated-orcid":false,"given":"Albert","family":"Ros-Lucas","sequence":"first","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"Campus Mar, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain"},{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7107-5374","authenticated-orcid":false,"given":"Nieves","family":"Mart\u00ednez-Peinado","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Secci\u00f3 de Parasitologia, Departament de Biologia, Sanitat i Medi Ambient, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2525-0263","authenticated-orcid":false,"given":"Juan Carlos","family":"Gabald\u00f3n-Figueira","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Clinical Microbiology, Hospital de la Santa Creu i Sant Pau, 08025 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Morillo-Osorio","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9930-3225","authenticated-orcid":false,"given":"Cristina","family":"Ballart","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Secci\u00f3 de Parasitologia, Departament de Biologia, Sanitat i Medi Ambient, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8143-9773","authenticated-orcid":false,"given":"Montserrat","family":"G\u00e1llego","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Secci\u00f3 de Parasitologia, Departament de Biologia, Sanitat i Medi Ambient, Facultat de Farm\u00e0cia i Ci\u00e8ncies de l\u2019Alimentaci\u00f3, Universitat de Barcelona, 08028 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4237-1075","authenticated-orcid":false,"given":"Mar\u00eda-Jes\u00fas","family":"Pinazo","sequence":"additional","affiliation":[{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Drugs for Neglected Diseases Initiative (DNDi), Rio de Janeiro 20010-020, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5045-1585","authenticated-orcid":false,"given":"Joaquim","family":"Gasc\u00f3n","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4422-241X","authenticated-orcid":false,"given":"Ana","family":"Requena-M\u00e9ndez","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Medicine Solna, Karolinska Institute, 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4466-7969","authenticated-orcid":false,"given":"Julio","family":"Alonso-Padilla","sequence":"additional","affiliation":[{"name":"ISGlobal, 08036 Barcelona, Spain"},{"name":"CIBERINFEC, ISCIII\u2013CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"INTERTRYP, University of Montpellier, CIRAD, IRD, 34398 Montpellier, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref_1","unstructured":"(2026, May 15). Chagas Disease. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/chagas-disease-(american-trypanosomiasis)."},{"key":"ref_2","unstructured":"(2026, May 15). Updated Estimate of Chagas Disease in the Endemic Countries of the Americas 2018. Available online: https:\/\/iris.paho.org\/items\/cd0ec286-92c9-4a2d-9b11-c1d2c08249b4."},{"key":"ref_3","unstructured":"(2026). GBD 2023 Chagas Disease and RAISE Study Collaborators. Global, Regional, and National Burden of Chagas Disease, 1990\u20132023: A Systematic Analysis for the Global Burden of Disease Study 2023. Lancet. Infect. Dis., 26, 284\u2013301."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2632658","DOI":"10.1080\/14760584.2026.2632658","article-title":"Vaccines against Chronic Trypanosoma cruzi Infection: Progress, Challenges and Future Directions","volume":"25","author":"Dumonteil","year":"2026","journal-title":"Expert Rev. Vaccines"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4896","DOI":"10.1128\/AAC.00537-10","article-title":"Tolerance of Benznidazole in Treatment of Chagas\u2019 Disease in Adults","volume":"54","author":"Pinazo","year":"2010","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"104851","DOI":"10.1016\/j.compbiomed.2021.104851","article-title":"In Silico Methods and Tools for Drug Discovery","volume":"137","author":"Shaker","year":"2021","journal-title":"Comput. Biol. Med."},{"key":"ref_7","unstructured":"G\u00f3mez, K.A., and Buscaglia, C.A. (2026). Computer-Aided Discovery of Drugs against Chagas Disease. T. cruzi Infection: Methods and Protocols, Springer."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4703","DOI":"10.1038\/srep04703","article-title":"Nitroheterocyclic Compounds Are More Efficacious than CYP51 Inhibitors against Trypanosoma cruzi: Implications for Chagas Disease Drug Discovery and Development","volume":"4","author":"Moraes","year":"2014","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1899","DOI":"10.1056\/NEJMoa1313122","article-title":"Randomized Trial of Posaconazole and Benznidazole for Chronic Chagas\u2019 Disease","volume":"370","author":"Molina","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S1473-3099(17)30538-8","article-title":"Treatment of Adult Chronic Indeterminate Chagas Disease with Benznidazole and Three E1224 Dosing Regimens: A Proof-of-Concept, Randomised, Placebo-Controlled Trial","volume":"18","author":"Torrico","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1080\/14728222.2023.2264512","article-title":"Molecular Targets for Chagas Disease: Validation, Challenges and Lead Compounds for Widely Exploited Targets","volume":"27","author":"Lapierre","year":"2023","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Tabana, Y., Babu, D., Fahlman, R., Siraki, A.G., and Barakat, K. (2023). Target Identification of Small Molecules: An Overview of the Current Applications in Drug Discovery. BMC Biotechnol., 23.","DOI":"10.1186\/s12896-023-00815-4"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"175","DOI":"10.2147\/DDDT.S16381","article-title":"Drug Discovery and Development for Neglected Diseases: The DNDi Model","volume":"5","author":"Ioset","year":"2011","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Galati, S., Di Stefano, M., Martinelli, E., Poli, G., and Tuccinardi, T. (2021). Recent Advances in In Silico Target Fishing. Molecules, 26.","DOI":"10.3390\/molecules26175124"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ros-Lucas, A., Martinez-Peinado, N., Bastida, J., Gasc\u00f3n, J., and Alonso-Padilla, J. (2022). The Use of AlphaFold for In Silico Exploration of Drug Targets in the Parasite Trypanosoma cruzi. Front. Cell. Infect. Microbiol., 12.","DOI":"10.3389\/fcimb.2022.944748"},{"key":"ref_16","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_17","doi-asserted-by":"crossref","first-page":"168967","DOI":"10.1016\/j.jmb.2025.168967","article-title":"AlphaFold Protein Structure Database and 3D-Beacons: New Data and Capabilities","volume":"437","author":"Fleming","year":"2025","journal-title":"J. Mol. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"eaag1166","DOI":"10.1126\/scitranslmed.aag1166","article-title":"The Druggable Genome and Support for Target Identification and Validation in Drug Development","volume":"9","author":"Finan","year":"2017","journal-title":"Sci. Transl. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3049","DOI":"10.1016\/j.apsb.2022.02.002","article-title":"Why 90% of Clinical Drug Development Fails and How to Improve It?","volume":"12","author":"Sun","year":"2022","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1111\/jeu.12747","article-title":"State-of-the-art CRISPR \/Cas9 Technology for Genome Editing in Trypanosomatids","volume":"66","author":"Lander","year":"2019","journal-title":"J. Eukaryot. Microbiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e2416009122","DOI":"10.1073\/pnas.2416009122","article-title":"A Limitation Lifted: A Conditional Knockdown System Reveals Essential Roles for Polo-like Kinase and Aurora Kinase 1 in Trypanosoma cruzi Cell Division","volume":"122","author":"Wiedeman","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/bs.apha.2025.01.011","article-title":"Targeting Disease: Computational Approaches for Drug Target Identification","volume":"Volume 103","author":"Puniani","year":"2025","journal-title":"Advances in Pharmacology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1021\/acs.jcim.8b00832","article-title":"Advances and Challenges in Computational Target Prediction","volume":"59","author":"Sydow","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"W357","DOI":"10.1093\/nar\/gkz382","article-title":"SwissTargetPrediction: Updated Data and New Features for Efficient Prediction of Protein Targets of Small Molecules","volume":"47","author":"Daina","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Krause, F., Voigt, K., Di Ventura, B., and \u00d6zt\u00fcrk, M.A. (2023). ReverseDock: A Web Server for Blind Docking of a Single Ligand to Multiple Protein Targets Using AutoDock Vina. Front. Mol. Biosci., 10.","DOI":"10.3389\/fmolb.2023.1243970"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1021\/acs.jcim.8b00524","article-title":"Polypharmacology Browser PPB2: Target Prediction Combining Nearest Neighbors with Machine Learning","volume":"59","author":"Awale","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"D1180","DOI":"10.1093\/nar\/gkad1004","article-title":"The ChEMBL Database in 2023: A Drug Discovery Platform Spanning Multiple Bioactivity Data Types and Time Periods","volume":"52","author":"Zdrazil","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D1633","DOI":"10.1093\/nar\/gkae1075","article-title":"BindingDB in 2024: A FAIR Knowledgebase of Protein-Small Molecule Binding Data","volume":"53","author":"Liu","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1021\/acs.accounts.6b00491","article-title":"Forging the Basis for Developing Protein\u2013Ligand Interaction Scoring Functions","volume":"50","author":"Liu","year":"2017","journal-title":"Acc. Chem. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1038\/nature08506","article-title":"Predicting New Molecular Targets for Known Drugs","volume":"462","author":"Keiser","year":"2009","journal-title":"Nature"},{"key":"ref_32","unstructured":"Landrum, G., Tosco, P., Kelley, B., Rodriguez, R., Cosgrove, D., Vianello, R., Gedeck, P., Jones, G., and Kawashima, E. (2026). Rdkit\/Rdkit: 2025_09_6 (Q3 2025) Release. Zenodo."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1021\/ci050457y","article-title":"ErG: 2D Pharmacophore Descriptions for Scaffold Hopping","volume":"46","author":"Stiefl","year":"2006","journal-title":"J. Chem. Inf. Model."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1126\/science.1112631","article-title":"The Genome Sequence of Trypanosoma cruzi, Etiologic Agent of Chagas Disease","volume":"309","author":"Myler","year":"2005","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/s41596-025-01189-x","article-title":"A Graphic and Command Line Protocol for Quick and Accurate Comparisons of Protein and Nucleic Acid Structures with US-align","volume":"21","author":"Zhang","year":"2026","journal-title":"Nat. Protoc."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1126\/science.1112181","article-title":"Comparative Genomics of Trypanosomatid Parasitic Protozoa","volume":"309","author":"Myler","year":"2005","journal-title":"Science"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mej\u00eda-Jaramillo, A.M., Ospina-Zapata, H., Fernandez, G.J., and Triana-Ch\u00e1vez, O. (2025). Transcriptomic Analysis of Benznidazole-Resistant Trypanosoma cruzi Clone Reveals Nitroreductase I-independent Resistance Mechanisms. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0314189"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nature19339","article-title":"Proteasome Inhibition for Treatment of Leishmaniasis, Chagas Disease and Sleeping Sickness","volume":"537","author":"Khare","year":"2016","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Martinez-Peinado, N., Martori, C., Cortes-Serra, N., Sherman, J., Rodriguez, A., Gascon, J., Alberola, J., Pinazo, M.J., Rodriguez-Cortes, A., and Alonso-Padilla, J. (2021). Anti-Trypanosoma cruzi Activity of Metabolism Modifier Compounds. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22020688"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Begolo, D., Vincent, I.M., Giordani, F., P\u00f6hner, I., Witty, M.J., Rowan, T.G., Bengaly, Z., Gillingwater, K., Freund, Y., and Wade, R.C. (2018). The Trypanocidal Benzoxaborole AN7973 Inhibits Trypanosome mRNA Processing. PLoS Pathog., 14.","DOI":"10.1101\/295550"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1536","DOI":"10.1038\/s41564-022-01211-y","article-title":"Discovery of an Orally Active Benzoxaborole Prodrug Effective in the Treatment of Chagas Disease in Non-Human Primates","volume":"7","author":"Padilla","year":"2022","journal-title":"Nat. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1021\/acs.jmedchem.5c02459","article-title":"Discovery of IID432 for Chagas Disease: A Cyanotriazole Inhibitor of Trypanosoma cruzi Topoisomerase II Achieves Sterile Cure After Short-Term Treatment in a Chronic Infection Model","volume":"69","author":"Saldivia","year":"2026","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1038\/s41564-020-0745-6","article-title":"Targeting the Trypanosome Kinetochore with CLK1 Protein Kinase Inhibitors","volume":"5","author":"Saldivia","year":"2020","journal-title":"Nat. Microbiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1186\/s13071-020-04171-6","article-title":"Amaryllidaceae Alkaloids with Anti-Trypanosoma cruzi Activity","volume":"13","author":"Pinazo","year":"2020","journal-title":"Parasites Vectors"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Martinez-Peinado, N., Cortes-Serra, N., Sherman, J., Rodriguez, A., Bustamante, J.M., Gascon, J., Pinazo, M.J., and Alonso-Padilla, J. (2021). Identification of Trypanosoma cruzi Growth Inhibitors with Activity In Vivo within a Collection of Licensed Drugs. Microorganisms, 9.","DOI":"10.3390\/microorganisms9020406"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1093\/bioinformatics\/btq066","article-title":"How Significant Is a Protein Structure Similarity with TM-score = 0.5?","volume":"26","author":"Xu","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_47","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. Part A Mol. Integr. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Beltran-Hortelano, I., Perez-Silanes, S., and Galiano, S. (2017). Trypanothione Reductase and Superoxide Dismutase as Current Drug Targets for Trypanosoma cruzi: An Overview of Compounds with Activity against Chagas Disease. Curr. Med. Chem., 24.","DOI":"10.2174\/0929867323666161227094049"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2664","DOI":"10.1128\/AAC.02185-15","article-title":"Putative Role of the Aldo-Keto Reductase from Trypanosoma cruzi in Benznidazole Metabolism","volume":"60","author":"Garavaglia","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.exppara.2014.03.013","article-title":"Trypanosomacruzi Chemical Proteomics Using Immobilized Benznidazole","volume":"140","author":"Trochine","year":"2014","journal-title":"Exp. Parasitol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.molbiopara.2008.03.007","article-title":"Multiple NADPH\u2013Cytochrome P450 Reductases from Trypanosoma cruzi","volume":"160","author":"Portal","year":"2008","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"8771","DOI":"10.1038\/srep08771","article-title":"New Compound Sets Identified from High Throughput Phenotypic Screening against Three Kinetoplastid Parasites: An Open Resource","volume":"5","author":"Cantizani","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10773","DOI":"10.1021\/acs.jmedchem.0c00499","article-title":"Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases","volume":"63","author":"Nagle","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"101996","DOI":"10.1016\/j.isci.2020.101996","article-title":"17-DMAG Dually Inhibits Hsp90 and Histone Lysine Demethylases in Alveolar Rhabdomyosarcoma","volume":"24","author":"Singh","year":"2021","journal-title":"iScience"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1126\/science.adh0614","article-title":"Cyanotriazoles Are Selective Topoisomerase II Poisons That Rapidly Cure Trypanosome Infections","volume":"380","author":"Rao","year":"2023","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"10206","DOI":"10.1073\/pnas.0500926102","article-title":"The Structure of the 80S Ribosome from Trypanosoma cruzi Reveals Unique rRNA Components","volume":"102","author":"Gao","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.pt.2016.12.003","article-title":"Ribosome Assembly in Trypanosomatids: A Novel Therapeutic Target","volume":"33","author":"Kamina","year":"2017","journal-title":"Trends Parasitol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1038\/nchembio.2007.59","article-title":"High-Content Single-Cell Drug Screening with Phosphospecific Flow Cytometry","volume":"4","author":"Krutzik","year":"2008","journal-title":"Nat. Chem. Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.4161\/cc.9.14.12372","article-title":"Molecular Cloning and Characterization of Mitogen-Activated Protein Kinase 2 in Trypanosoma cruzi","volume":"9","author":"Bao","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Br\u00edgido, H.P.C., Dos Santos, L.G.A., De Barros, R.C., Correa-Barbosa, J., Santos, P.V.B.D., Paz, R.F.L., Pereira, A.R., Albuquerque, K.C.O.D., Campos, M.B., and Silveira, F.T. (2025). The Role of Oxidative Stress in the Pathogenesis and Treatment of Leishmaniasis: Impact on Drug Toxicity and Therapeutic Potential of Natural Products. Toxics, 13.","DOI":"10.3390\/toxics13030190"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"116365","DOI":"10.1016\/j.bmc.2021.116365","article-title":"Cysteine Proteases as Potential Targets for Anti-Trypanosomatid Drug Discovery","volume":"46","author":"Judice","year":"2021","journal-title":"Bioorganic Med. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1128\/AAC.48.3.852-859.2004","article-title":"Miltefosine Induces Apoptosis-like Death in Leishmania donovani Promastigotes","volume":"48","author":"Paris","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"W547","DOI":"10.1093\/nar\/gkaf394","article-title":"The UniProt Website API: Facilitating Programmatic Access to Protein Knowledge","volume":"53","author":"Ahmad","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_64","unstructured":"(2026, February 02). RSCB PDB-Ligand Mapping Script. Available online: https:\/\/github.com\/rcsb\/rcsb-training-resources\/blob\/master\/example-use-cases\/pdb-ligand-composition\/generate_pdb_ligand_mappings.py."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"D482","DOI":"10.1093\/nar\/gky1114","article-title":"SIFTS: Updated Structure Integration with Function, Taxonomy and Sequences Resource Allows 40-Fold Increase in Coverage of Structure-Based Annotations for Proteins","volume":"47","author":"Dana","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"D444","DOI":"10.1093\/nar\/gkae1082","article-title":"InterPro: The Protein Sequence Classification Resource in 2025","volume":"53","author":"Blum","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1093\/bioinformatics\/btl158","article-title":"Cd-Hit: A Fast Program for Clustering and Comparing Large Sets of Protein or Nucleotide Sequences","volume":"22","author":"Li","year":"2006","journal-title":"Bioinformatics"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Le Guilloux, V., Schmidtke, P., and Tuffery, P. (2009). Fpocket: An Open Source Platform for Ligand Pocket Detection. BMC Bioinform., 10.","DOI":"10.1186\/1471-2105-10-168"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13321-018-0285-8","article-title":"P2Rank: Machine Learning Based Tool for Rapid and Accurate Prediction of Ligand Binding Sites from Protein Structure","volume":"10","author":"Hoksza","year":"2018","journal-title":"J. Cheminform."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Shanmugasundram, A., Starns, D., B\u00f6hme, U., Amos, B., Wilkinson, P.A., Harb, O.S., Warrenfeltz, S., Kissinger, J.C., McDowell, M.A., and Roos, D.S. (2023). TriTrypDB: An Integrated Functional Genomics Resource for Kinetoplastida. PLoS Negl. Trop. Dis., 17.","DOI":"10.1371\/journal.pntd.0011058"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1038\/s41586-021-03828-1","article-title":"Highly Accurate Protein Structure Prediction for the Human Proteome","volume":"596","author":"Tunyasuvunakool","year":"2021","journal-title":"Nature"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1046\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T04:33:01Z","timestamp":1783571581000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/7\/1046"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,7]]},"references-count":71,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ph19071046"],"URL":"https:\/\/doi.org\/10.3390\/ph19071046","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,7]]}}}