{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T01:10:22Z","timestamp":1790298622850,"version":"4.1.0"},"reference-count":101,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T00:00:00Z","timestamp":1706918400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Universidad Cat\u00f3lica de Santa Mar\u00eda","award":["7309-CU-2020"],"award-info":[{"award-number":["7309-CU-2020"]}]},{"name":"Universidad Cat\u00f3lica de Santa Mar\u00eda","award":["24150-R-2017"],"award-info":[{"award-number":["24150-R-2017"]}]},{"name":"Universidad Cat\u00f3lica de Santa Mar\u00eda","award":["23824-R-2016"],"award-info":[{"award-number":["23824-R-2016"]}]},{"name":"Universidad Cat\u00f3lica de Santa Mar\u00eda","award":["27574-R-2020"],"award-info":[{"award-number":["27574-R-2020"]}]},{"name":"Universidad Cat\u00f3lica de Santa Mar\u00eda","award":["28048-R-2021"],"award-info":[{"award-number":["28048-R-2021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["TropicalMed"],"abstract":"<jats:p>Visceral Leishmaniasis (VL) has a high death rate, with 500,000 new cases and 50,000 deaths occurring annually. Despite the development of novel strategies and technologies, there is no adequate treatment for the disease. Therefore, the purpose of this study is to find structural analogs of natural products as potential novel drugs to treat VL. We selected structural analogs from natural products that have shown antileishmanial activities, and that may impede the purine salvage pathway using computer-aided drug-design (CADD) approaches. For these, we started with the vastly studied target in the pathway, the adenine phosphoribosyl transferase (APRT) protein, which alone is non-essential for the survival of the parasite. Keeping this in mind, we search for a substance that can bind to multiple targets throughout the pathway. Computational techniques were used to study the purine salvage pathway from Leishmania infantum, and molecular dynamic simulations were used to gather information on the interactions between ligands and proteins. Because of its low homology to human proteins and its essential role in the purine salvage pathway proteins network interaction, the findings further highlight the significance of adenylosuccinate lyase protein (ADL) as a therapeutic target. An analog of the alkaloid Skimmianine, N,N-diethyl-4-methoxy-1-benzofuran-6-carboxamide, demonstrated a good binding affinity to APRT and ADL targets, no expected toxicity, and potential for oral route administration. This study indicates that the compound may have antileishmanial activity, which was granted in vitro and in vivo experiments to settle this finding in the future.<\/jats:p>","DOI":"10.3390\/tropicalmed9020041","type":"journal-article","created":{"date-parts":[[2024,2,5]],"date-time":"2024-02-05T08:41:43Z","timestamp":1707122503000},"page":"41","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Targeting with Structural Analogs of Natural Products the Purine Salvage Pathway in Leishmania (Leishmania) infantum by Computer-Aided Drug-Design Approaches"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8791-0506","authenticated-orcid":false,"given":"Haruna Luz","family":"Barazorda-Ccahuana","sequence":"first","affiliation":[{"name":"Computational Biology and Chemistry Research Group, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9368-0329","authenticated-orcid":false,"given":"Eymi Gladys","family":"C\u00e1rcamo-Rodriguez","sequence":"additional","affiliation":[{"name":"Computational Biology and Chemistry Research Group, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Arequipa 04000, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8670-963X","authenticated-orcid":false,"given":"Angela Emperatriz","family":"Centeno-Lopez","sequence":"additional","affiliation":[{"name":"Computational Biology and Chemistry Research Group, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Arequipa 04000, Peru"},{"name":"Facultad de Ciencias Farmac\u00e9uticas, Bioqu\u00edmicas y Biotecnol\u00f3gicas, Universidad Cat\u00f3lica de Santa Mar\u00eda, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8890-3030","authenticated-orcid":false,"given":"Alexsandro Sobreira","family":"Galdino","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biotecnologia de Microrganismos, Universidade Federal S\u00e3o Jo\u00e3o Del-Rei, Divin\u00f3polis 35501-296, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1303-0490","authenticated-orcid":false,"given":"Ricardo Andrez","family":"Machado-de-\u00c1vila","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias da Sa\u00fade, Universidade do Extremo Sul Catarinense, Crici\u00fama 88806-000, SC, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4181-7546","authenticated-orcid":false,"given":"Rodolfo Cordeiro","family":"Giunchetti","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia das Intera\u00e7\u00f5es Celulares, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil"},{"name":"Instituto Nacional de Ci\u00eancia e Tecnologia em Doen\u00e7as Tropicais, INCT-DT, Salvador 40015-970, BA, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3991-9343","authenticated-orcid":false,"given":"Eduardo Antonio Ferraz","family":"Coelho","sequence":"additional","affiliation":[{"name":"Programa de P\u00f3s-Gradua\u00e7\u00e3o em Ci\u00eancias da Sa\u00fade: Infectologia e Medicina Tropical, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil"},{"name":"Departamento de Patologia Cl\u00ednica, COLTEC, Universidade Federal de Minas Gerais, Belo Horizonte 31270-901, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8394-4802","authenticated-orcid":false,"given":"Miguel Angel","family":"Ch\u00e1vez-Fumagalli","sequence":"additional","affiliation":[{"name":"Computational Biology and Chemistry Research Group, Vicerrectorado de Investigaci\u00f3n, Universidad Cat\u00f3lica de Santa Mar\u00eda, Arequipa 04000, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Ece, A. (2023). Computer-aided drug design. BMC Chem., 17.","DOI":"10.1186\/s13065-023-00939-w"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"10375","DOI":"10.1021\/acs.jmedchem.8b00407","article-title":"Lead-like drugs: A perspective: Miniperspective","volume":"61","author":"Raymer","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1021\/jm010548w","article-title":"Molecular docking and high-throughput screening for novel inhibitors of protein tyrosine phosphatase-1B","volume":"45","author":"Doman","year":"2002","journal-title":"J. Med. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1136\/bmj.325.7357.176","article-title":"The world\u2019s most neglected diseases","volume":"325","author":"Yamey","year":"2002","journal-title":"BMJ"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1459","DOI":"10.1016\/S0140-6736(16)31012-1","article-title":"Global, regional, and national life expectancy, all-cause and cause-specific mortality for 249 causes of death, 1980\u20132015: A systematic analysis for the Global Burden of Disease Study 2015","volume":"388","author":"Uthman","year":"2016","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1016\/S0140-6736(18)32335-3","article-title":"Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990\u20132017: A systematic analysis for the Global Burden of Disease Study 2017","volume":"392","author":"Kyu","year":"2018","journal-title":"Lancet"},{"key":"ref_7","unstructured":"Ready, P.D. (2014). Clinical Epidemiology, Taylor & Francis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1016\/S0140-6736(18)31204-2","article-title":"Leishmaniasis","volume":"392","author":"Burza","year":"2018","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Scarpini, S., Dondi, A., Totaro, C., Biagi, C., Melchionda, F., Zama, D., Pierantoni, L., Gennari, M., Campagna, C., and Prete, A. (2022). Visceral leishmaniasis: Epidemiology, diagnosis, and treatment regimens in different geographical areas with a focus on pediatrics. Microorganisms, 10.","DOI":"10.3390\/microorganisms10101887"},{"key":"ref_10","unstructured":"Lindoso, J.A.L., Costa, J.M.L., Queiroz, I.T., and Goto, H. (2012). Research and Reports in Tropical Medicine, Taylor & Francis."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Olias-Molero, A.I., de la Fuente, C., Cuquerella, M., Torrado, J.J., and Alunda, J.M. (2021). Antileishmanial drug discovery and development: Time to reset the model?. Microorganisms, 9.","DOI":"10.3390\/microorganisms9122500"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4625","DOI":"10.1007\/s00436-015-4708-4","article-title":"Antileishmanial activity and evaluation of the mechanism of action of strychnobiflavone flavonoid isolated from Strychnos pseudoquina against Leishmania infantum","volume":"114","author":"Lage","year":"2015","journal-title":"Parasitol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.jep.2015.02.047","article-title":"Antileishmanial activity of standardized fractions of Stryphnodendron obovatum (Barbatim\u00e3o) extract and constituent compounds","volume":"165","author":"Ribeiro","year":"2015","journal-title":"J. Ethnopharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"304354","DOI":"10.1155\/2013\/304354","article-title":"Strychnos pseudoquina and its purified compounds present an effective in vitro antileishmanial activity","volume":"2013","author":"Lage","year":"2013","journal-title":"Evid.-Based Complement. Altern. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.parint.2011.06.001","article-title":"Leishmanicidal activity of the Agaricus blazei Murill in different Leishmania species","volume":"60","author":"Valadares","year":"2011","journal-title":"Parasitol. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1007\/s00436-012-3028-1","article-title":"Therapeutic efficacy induced by the oral administration of Agaricus blazei Murill against Leishmania amazonensis","volume":"111","author":"Valadares","year":"2012","journal-title":"Parasitol. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.exppara.2014.05.004","article-title":"Antileishmanial activity and cytotoxicity of Brazilian plants","volume":"143","author":"Ribeiro","year":"2014","journal-title":"Exp. Parasitol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural products as sources of new drugs over the nearly four decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1007\/s00436-020-06736-x","article-title":"An overview of biochemically characterized drug targets in metabolic pathways of Leishmania parasite","volume":"119","author":"Raj","year":"2020","journal-title":"Parasitol. Res."},{"key":"ref_20","unstructured":"Makhoba, X.H., Viegas, C., Mosa, R.A., Viegas, F.P., and Pooe, O.J. (2020). Drug Design, Development and Therapy, Taylor & Francis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.ddtec.2006.09.004","article-title":"New technologies in computer-aided drug design: Toward target identification and new chemical entity discovery","volume":"3","author":"Tang","year":"2006","journal-title":"Drug Discov. Today Technol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.jmgm.2018.11.014","article-title":"In silico Leishmania proteome mining applied to identify drug target potential to be used to treat against visceral and tegumentary leishmaniasis","volume":"87","author":"Lage","year":"2019","journal-title":"J. Mol. Graph. Model."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12639-018-1061-4","article-title":"Dependence of Leishmania parasite on host derived ATP: An overview of extracellular nucleotide metabolism in parasite","volume":"43","author":"Arora","year":"2019","journal-title":"J. Parasit. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Hofer, A. (2023). Targeting the nucleotide metabolism of Trypanosoma brucei and other trypanosomatids. FEMS Microbiol. Rev., 47.","DOI":"10.1093\/femsre\/fuad020"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Soni, M., and Pratap, J.V. (2022). Development of novel anti-leishmanials: The case for structure-based approaches. Pathogens, 11.","DOI":"10.3390\/pathogens11080950"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.2174\/092986710791556023","article-title":"Inhibitors of the purine salvage pathway: A valuable approach for antiprotozoal chemotherapy?","volume":"17","author":"Berg","year":"2010","journal-title":"Curr. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3670","DOI":"10.1073\/pnas.76.8.3670","article-title":"Adenine aminohydrolase: Occurrence and possible significance in Trypanosomid flagellates","volume":"76","author":"Kidder","year":"1979","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Singh, S., and Prajapati, V.K. (2022). Exploring actinomycetes natural products to identify potential multi-target inhibitors against Leishmania donovani. 3 Biotech, 12.","DOI":"10.1007\/s13205-022-03304-1"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"8548","DOI":"10.1021\/acsomega.1c00366","article-title":"Antileishmanial evaluation of bark methanolic extract of Acacia nilotica: In vitro and in silico studies","volume":"6","author":"Ali","year":"2021","journal-title":"ACS Omega"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1002\/pca.3213","article-title":"Computational multi-target approach to target essential enzymes of Leishmania donovani using comparative molecular dynamic simulations and MMPBSA analysis","volume":"34","author":"Saha","year":"2023","journal-title":"Phytochem. Anal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100048","DOI":"10.1016\/j.jvacx.2019.100048","article-title":"Allopurinol therapy provides long term clinical improvement, but additional immunotherapy is required for sustained parasite clearance, in L. infantum-infected dogs","volume":"4","author":"Nascimento","year":"2020","journal-title":"Vaccine X"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s12639-010-0006-3","article-title":"Drug targets in Leishmania","volume":"34","author":"Chawla","year":"2010","journal-title":"J. Parasit. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7215","DOI":"10.1038\/s41598-017-07451-x","article-title":"NuBBEDB: An updated database to uncover chemical and biological information from Brazilian biodiversity","volume":"7","author":"Pilon","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D158","DOI":"10.1093\/nar\/gkw1099","article-title":"UniProt: The universal protein knowledgebase","volume":"45","author":"Apweiler","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"W29","DOI":"10.1093\/nar\/gkt282","article-title":"BLAST: A more efficient report with usability improvements","volume":"41","author":"Boratyn","year":"2013","journal-title":"Nucleic Acids Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1093\/molbev\/mst012","article-title":"Building phylogenetic trees from molecular data with MEGA","volume":"30","author":"Hall","year":"2013","journal-title":"Mol. Biol. Evol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"W293","DOI":"10.1093\/nar\/gkab301","article-title":"Interactive Tree Of Life (iTOL) v5: An online tool for phylogenetic tree display and annotation","volume":"49","author":"Letunic","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"D447","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10: Protein\u2013protein interaction networks, integrated over the tree of life","volume":"43","author":"Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","unstructured":"Chin, C.H., Chen, S.H., Wu, H.H., Ho, C.W., Ko, M.T., and Lin, C.Y. (2014). cytoHubba: Identifying hub objects and sub-networks from complex interactome. BMC Syst. Biol., 8.","DOI":"10.1186\/1752-0509-8-S4-S11"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1093\/bioinformatics\/4.1.67","article-title":"The significance of protein sequence similarities","volume":"4","author":"Collins","year":"1988","journal-title":"Bioinformatics"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/S0076-6879(96)66017-0","article-title":"[15] Effective protein sequence comparison","volume":"Volume 266","author":"Pearson","year":"1996","journal-title":"Methods in Enzymology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2811","DOI":"10.1093\/bioinformatics\/btu393","article-title":"\u201cCirclize\u201d implements and enhances circular visualization in R","volume":"30","author":"Gu","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1038\/sj.hdy.6800737","article-title":"Wolbachia variant that induces two distinct reproductive phenotypes in different hosts","volume":"95","author":"Sasaki","year":"2005","journal-title":"Heredity"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"93","DOI":"10.12688\/f1000research.129943.2","article-title":"Computer-aided drug design approaches applied to screen natural product\u2019s structural analogs targeting arginase in Leishmania spp","volume":"12","author":"Puma","year":"2023","journal-title":"F1000Research"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"D1102","DOI":"10.1093\/nar\/gky1033","article-title":"PubChem 2019 update: Improved access to chemical data","volume":"47","author":"Kim","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1021\/acs.jcim.6b00174","article-title":"SwissSimilarity: A web tool for low to ultra high throughput ligand-based virtual screening","volume":"56","author":"Zoete","year":"2016","journal-title":"J. Chem. Inf. Model."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1021\/ci500588j","article-title":"DataWarrior: An open-source program for chemistry aware data visualization and analysis","volume":"55","author":"Sander","year":"2015","journal-title":"J. Chem. Inf. Model."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.jbiotec.2017.07.028","article-title":"KNIME for reproducible cross-domain analysis of life science data","volume":"261","author":"Fillbrunn","year":"2017","journal-title":"J. Biotechnol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1093\/nar\/gkg520","article-title":"SWISS-MODEL: An automated protein homology-modeling server","volume":"31","author":"Schwede","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"ref_51","unstructured":"Dallakyan, S., and Olson, A.J. (2015). Chemical Biology: Methods and Protocols, Springer."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1093\/bioinformatics\/btn307","article-title":"ChemmineR: A compound mining framework for R","volume":"24","author":"Cao","year":"2008","journal-title":"Bioinformatics"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/1758-2946-4-17","article-title":"Avogadro: An advanced semantic chemical editor, visualization, and analysis platform","volume":"4","author":"Hanwell","year":"2012","journal-title":"J. Cheminform."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3198","DOI":"10.1038\/s41598-021-82410-1","article-title":"New machine learning and physics-based scoring functions for drug discovery","volume":"11","author":"Guedes","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1021\/acs.jcim.9b00905","article-title":"Highly flexible ligand docking: Benchmarking of the DockThor program on the LEADS-PEP protein\u2013peptide data set","volume":"60","author":"Santos","year":"2020","journal-title":"J. Chem. Inf. Model."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1859","DOI":"10.1002\/jcc.20945","article-title":"CHARMM-GUI: A web-based graphical user interface for CHARMM","volume":"29","author":"Jo","year":"2008","journal-title":"J. Comput. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/jcc.21287","article-title":"CHARMM: The biomolecular simulation program","volume":"30","author":"Brooks","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Lee, J., Cheng, X., Jo, S., MacKerell, A.D., Klauda, J.B., and Im, W. (2016). CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM\/OpenMM simulations using the CHARMM36 additive force field. Biophys. J., 110.","DOI":"10.1016\/j.bpj.2015.11.3431"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1701","DOI":"10.1002\/jcc.20291","article-title":"GROMACS: Fast, flexible, and free","volume":"26","author":"Lindahl","year":"2005","journal-title":"J. Comput. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"2135","DOI":"10.1002\/jcc.23354","article-title":"CHARMM36 all-atom additive protein force field: Validation based on comparison to NMR data","volume":"34","author":"Huang","year":"2013","journal-title":"J. Comput. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"3314","DOI":"10.1021\/ct300418h","article-title":"MMPBSA. py: An efficient program for end-state free energy calculations","volume":"8","author":"Miller","year":"2012","journal-title":"J. Chem. Theory Comput."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1038\/s41597-020-0451-5","article-title":"An interactive database of Leishmania species distribution in the Americas","volume":"7","author":"Giovanny","year":"2020","journal-title":"Sci. Data"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"3137","DOI":"10.1158\/1535-7163.MCT-10-0642","article-title":"Proof of concept: Network and systems biology approaches aid in the discovery of potent anticancer drug combinations","volume":"9","author":"Azmi","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1520","DOI":"10.2174\/092986708784638843","article-title":"What does systems biology mean for drug development?","volume":"15","author":"Schrattenholz","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"o1503","DOI":"10.1107\/S1600536803019913","article-title":"Redetermination of skimmianine: A new inhibitor against the Leishmania APRT enzyme","volume":"59","author":"Napolitano","year":"2003","journal-title":"Acta Crystallogr. Sect. E Struct. Rep. Online"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1515\/znc-2008-5-611","article-title":"Enzymatic inhibitory activity and trypanocidal effects of extracts and compounds from Siphoneugena densiflora O. Berg and Vitex polygama Cham","volume":"63","author":"Gallo","year":"2008","journal-title":"Z. Naturforschung C"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1134\/S0026893308040195","article-title":"Radius of gyration as an indicator of protein structure compactness","volume":"42","author":"Lobanov","year":"2008","journal-title":"Mol. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1007\/s00894-009-0454-9","article-title":"Solvent accessible surface area approximations for rapid and accurate protein structure prediction","volume":"15","author":"Durham","year":"2009","journal-title":"J. Mol. Model."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Alvar, J., V\u00e9lez, I.D., Bern, C., Herrero, M., Desjeux, P., Cano, J., Jannin, J., Boer, M.d., and Team, W.L.C. (2012). Leishmaniasis worldwide and global estimates of its incidence. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035671"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.idc.2012.03.005","article-title":"Visceral leishmaniasis","volume":"26","author":"Diro","year":"2012","journal-title":"Infect. Dis. Clin."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.idc.2018.10.005","article-title":"Visceral leishmaniasis: Recent advances in diagnostics and treatment regimens","volume":"33","author":"Diro","year":"2019","journal-title":"Infect. Dis. Clin."},{"key":"ref_74","first-page":"530","article-title":"Global leishmaniasis surveillance, 2017\u20132018, and first report on 5 additional indicators","volume":"3","author":"Africa","year":"2018","journal-title":"Glob. Health"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Hotez, P.J., Aksoy, S., Brindley, P.J., and Kamhawi, S. (2020). World neglected tropical diseases day. PLoS Neglected Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0007999"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1080\/14760584.2021.1990043","article-title":"Overcoming roadblocks in the development of vaccines for leishmaniasis","volume":"20","author":"Kaye","year":"2021","journal-title":"Expert Rev. Vaccines"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1590\/0037-8682-0138-2015","article-title":"New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment","volume":"48","year":"2015","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1590\/0037-8682-0096-2015","article-title":"Theranostic applications of phage display to control leishmaniasis: Selection of biomarkers for serodiagnostics, vaccination, and immunotherapy","volume":"48","author":"Coelho","year":"2015","journal-title":"Rev. Soc. Bras. Med. Trop."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/s41586-018-0327-4","article-title":"Challenges and recent progress in drug discovery for tropical diseases","volume":"559","author":"Duce","year":"2018","journal-title":"Nature"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.3389\/fchem.2020.579891","article-title":"Use of natural products in leishmaniasis chemotherapy: An overview","volume":"8","author":"Gervazoni","year":"2020","journal-title":"Front. Chem."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Carter, N.S., Stamper, B.D., Elbarbry, F., Nguyen, V., Lopez, S., Kawasaki, Y., Poormohamadian, R., and Roberts, S.C. (2021). Natural products that target the arginase in Leishmania parasites hold therapeutic promise. Microorganisms, 9.","DOI":"10.3390\/microorganisms9020267"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.4155\/fmc-2017-0294","article-title":"The polypharmacology of natural products","volume":"10","author":"Ho","year":"2018","journal-title":"Future Med. Chem."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1186\/s13321-020-00450-7","article-title":"A review of computational drug repositioning: Strategies, approaches, opportunities, challenges, and directions","volume":"12","author":"Jarada","year":"2020","journal-title":"J. Cheminform."},{"key":"ref_84","first-page":"322","article-title":"Trypanocidal potentialities of skimmianine an alkaloid isolated from Zanthoxylum pistaciifolium griseb leaves","volume":"12","author":"Diaz","year":"2020","journal-title":"Pharmacogn. Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"556","DOI":"10.2174\/1573406419666221213124847","article-title":"Skimmianine: Natural Occurrence, Biosynthesis, Synthesis, Pharmacology and Pharmacokinetics","volume":"19","author":"Son","year":"2023","journal-title":"Med. Chem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1017\/S0031182011001168","article-title":"Leishmanicidal effect of Spiranthera odorat\u00edssima (Rutaceae) and its isolated alkaloid skimmianine occurs by a nitric oxide dependent mechanism","volume":"138","author":"Batista","year":"2011","journal-title":"Parasitology"},{"key":"ref_87","first-page":"439","article-title":"In vitro and in vivo activities of Haplophyllum myrtifolium against Leishmania tropica","volume":"30","year":"2007","journal-title":"New Microbiol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1002\/ptr.2650080312","article-title":"Antiprotozoal activity of quinoline alkaloids isolated from Galipea longiflora, a Bolivian plant used as a treatment for cutaneous leishmaniasis","volume":"8","author":"Fournet","year":"1994","journal-title":"Phytother. Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1038\/aps.2012.109","article-title":"Computational drug discovery","volume":"33","author":"Lu","year":"2012","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez, O.L., Diaz-Toro, Y., Ovalle, C., Valderrama, L., Muvdi, S., Rodr\u00edguez, I., Gomez, M.A., and Saravia, N.G. (2014). Miltefosine and antimonial drug susceptibility of Leishmania Viannia species and populations in regions of high transmission in Colombia. PLoS Neglected Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0002871"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"7626","DOI":"10.1074\/jbc.M111.307884","article-title":"Adenine aminohydrolase from Leishmania donovani: Unique enzyme in parasite purine metabolism","volume":"287","author":"Boitz","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"8977","DOI":"10.1074\/jbc.M112.431486","article-title":"Adenylosuccinate synthetase and adenylosuccinate lyase deficiencies trigger growth and infectivity deficits in Leishmania donovani","volume":"288","author":"Boitz","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"16084","DOI":"10.1074\/jbc.M600188200","article-title":"A conditional mutant deficient in hypoxanthine-guanine phosphoribosyltransferase and xanthine phosphoribosyltransferase validates the purine salvage pathway of Leishmania donovani","volume":"281","author":"Boitz","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.molbiopara.2006.02.015","article-title":"Leishmania donovani singly deficient in HGPRT, APRT or XPRT are viable in vitro and within mammalian macrophages","volume":"148","author":"Boitz","year":"2006","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e01010","DOI":"10.1590\/s2175-97902018000001010","article-title":"Drug discovery and computational strategies in the multitarget drugs era","volume":"54","author":"Viana","year":"2018","journal-title":"Braz. J. Pharm. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Senthilvel, P., Lavanya, P., Kumar, K.M., Swetha, R., Anitha, P., Bag, S., Sarveswari, S., Vijayakumar, V., Ramaiah, S., and Anbarasu, A. (2013). Flavonoid from Carica papaya inhibits NS2B-NS3 protease and prevents Dengue 2 viral assembly. Bioinformation, 9.","DOI":"10.6026\/97320630009889"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1002\/cmdc.201300399","article-title":"Toward the development of dual-targeted glyceraldehyde-3-phosphate dehydrogenase\/trypanothione reductase inhibitors against Trypanosoma brucei and Trypanosoma cruzi","volume":"9","author":"Belluti","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5196","DOI":"10.2174\/1381612822666160513144853","article-title":"Structure-and ligand-based approaches to evaluate aporphynic alkaloids from annonaceae as multi-target agent against Leishmania donovani","volume":"22","author":"Scotti","year":"2016","journal-title":"Curr. Pharm. Des."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"18363","DOI":"10.1038\/s41598-023-45448-x","article-title":"Dual-target drugs against Leishmania donovani for potential novel therapeutics","volume":"13","author":"Bora","year":"2023","journal-title":"Sci. Rep."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"5550","DOI":"10.3390\/molecules19055550","article-title":"In-silico analyses of sesquiterpene-related compounds on selected Leishmania enzyme-based targets","volume":"19","author":"Bernal","year":"2014","journal-title":"Molecules"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"111660","DOI":"10.1016\/j.ejmech.2019.111660","article-title":"Multi-target drugs active against leishmaniasis: A paradigm of drug repurposing","volume":"183","author":"Braga","year":"2019","journal-title":"Eur. J. Med. Chem."}],"container-title":["Tropical Medicine and Infectious Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2414-6366\/9\/2\/41\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:54:13Z","timestamp":1760104453000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2414-6366\/9\/2\/41"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,3]]},"references-count":101,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["tropicalmed9020041"],"URL":"https:\/\/doi.org\/10.3390\/tropicalmed9020041","relation":{},"ISSN":["2414-6366"],"issn-type":[{"value":"2414-6366","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,3]]}}}