{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T05:38:06Z","timestamp":1787895486250,"version":"build-2784847793"},"reference-count":35,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T00:00:00Z","timestamp":1660089600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Council for Scientific and Technological Development (CNPq)","award":["2013\/07600-3"],"award-info":[{"award-number":["2013\/07600-3"]}]},{"name":"National Council for Scientific and Technological Development (CNPq)","award":["2019\/05967-3"],"award-info":[{"award-number":["2019\/05967-3"]}]},{"name":"Coordination for the Improvement of Higher Education Personnel (CAPES)","award":["2013\/07600-3"],"award-info":[{"award-number":["2013\/07600-3"]}]},{"name":"Coordination for the Improvement of Higher Education Personnel (CAPES)","award":["2019\/05967-3"],"award-info":[{"award-number":["2019\/05967-3"]}]},{"name":"Sao Paulo Research Foundation (FAPESP)","award":["2013\/07600-3"],"award-info":[{"award-number":["2013\/07600-3"]}]},{"name":"Sao Paulo Research Foundation (FAPESP)","award":["2019\/05967-3"],"award-info":[{"award-number":["2019\/05967-3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Leishmaniasis is a neglected tropical disease that kills more than 20,000 people each year. The chemotherapy available for the treatment of the disease is limited, and novel approaches to discover novel drugs are urgently needed. Herein, 2D- and 4D-quantitative structure\u2013activity relationship (QSAR) models were developed for a series of oxazole and oxadiazole derivatives that are active against Leishmania infantum, the causative agent of visceral leishmaniasis. A clustering strategy based on structural similarity was applied with molecular fingerprints to divide the complete set of compounds into two groups. Hierarchical clustering was followed by the development of 2D- (R2 = 0.90, R2pred = 0.82) and 4D-QSAR models (R2 = 0.80, R2pred = 0.64), which showed improved statistical robustness and predictive ability.<\/jats:p>","DOI":"10.3390\/ijms23168898","type":"journal-article","created":{"date-parts":[[2022,8,10]],"date-time":"2022-08-10T09:42:56Z","timestamp":1660124576000},"page":"8898","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Hierarchical Clustering and Target-Independent QSAR for Antileishmanial Oxazole and Oxadiazole Derivatives"],"prefix":"10.3390","volume":"23","author":[{"given":"Henrique R.","family":"Teles","sequence":"first","affiliation":[{"name":"Laboratory of Medicinal and Computational Chemistry (LQMC), Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), Institute of Physics of S\u00e3o Carlos, University of S\u00e3o Paulo (USP), Av. Jo\u00e3o Dagnone, n\u00b0 1100, S\u00e3o Carlos 13563-120, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6947-0639","authenticated-orcid":false,"given":"Leonardo L. G.","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal and Computational Chemistry (LQMC), Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), Institute of Physics of S\u00e3o Carlos, University of S\u00e3o Paulo (USP), Av. Jo\u00e3o Dagnone, n\u00b0 1100, S\u00e3o Carlos 13563-120, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1106-183X","authenticated-orcid":false,"given":"Marilia","family":"Valli","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal and Computational Chemistry (LQMC), Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), Institute of Physics of S\u00e3o Carlos, University of S\u00e3o Paulo (USP), Av. Jo\u00e3o Dagnone, n\u00b0 1100, S\u00e3o Carlos 13563-120, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Coelho","sequence":"additional","affiliation":[{"name":"Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas, Campinas 13083-970, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0457-818X","authenticated-orcid":false,"given":"Adriano D.","family":"Andricopulo","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal and Computational Chemistry (LQMC), Center for Research and Innovation in Biodiversity and Drug Discovery (CIBFar), Institute of Physics of S\u00e3o Carlos, University of S\u00e3o Paulo (USP), Av. Jo\u00e3o Dagnone, n\u00b0 1100, S\u00e3o Carlos 13563-120, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,10]]},"reference":[{"key":"ref_1","first-page":"265","article-title":"Global leishmaniasis surveillance, 2017\u20132018, and first report on 5 additional indi cators\/Surveillance mondiale de la leishmaniose, 2017\u20132018, et premier rapport sur 5 indicateurs supplementaires","volume":"95","author":"Grout","year":"2020","journal-title":"Wkly. Epidemiol. Rec."},{"key":"ref_2","first-page":"277","article-title":"Leishmaniasis: Drug resistance and natural products","volume":"22","author":"Polonio","year":"2008","journal-title":"Int. J. Mol. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"31010","DOI":"10.1074\/jbc.M403959200","article-title":"Drug uptake and modulation of drug resistance in Leishmania by an aquaglyceroporin","volume":"279","author":"Gourbal","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112418","DOI":"10.1016\/j.ejmech.2020.112418","article-title":"Discovery of highly potent and selective antiparasitic new oxadiazole and hydroxy-oxindole small molecule hybrids","volume":"201","author":"Fernandes","year":"2020","journal-title":"Eur. J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7719","DOI":"10.1021\/jm400362b","article-title":"Drug discovery for neglected diseases: Molecular target-based and phenotypic approaches: Miniperspectives series on phenotypic screening for antiinfective targets","volume":"56","author":"Gilbert","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2278","DOI":"10.1016\/j.drudis.2022.04.004","article-title":"Approaches to advance drug discovery for neglected tropical diseases","volume":"27","author":"Ferreira","year":"2022","journal-title":"Drug Discov. Today"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.bioorg.2017.02.005","article-title":"Molecular hybridization conceded exceptionally potent quinolinyl-oxadiazole hybrids through phenyl linked thiosemicarbazide antileishmanial scaffolds: In silico validation and SAR studies","volume":"71","author":"Taha","year":"2017","journal-title":"Bioorganic Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1016\/j.ejmech.2016.12.019","article-title":"Synthesis and molecular modelling studies of phenyl linked oxadiazole-phenylhydrazone hybrids as potent antileishmanial agents","volume":"126","author":"Taha","year":"2017","journal-title":"Eur. J. Med. Chem."},{"key":"ref_9","first-page":"435","article-title":"1,2,4-and 1,3,4-Oxadiazoles as Scaffolds in the Development of Antiparasitic Agents","volume":"29","author":"Lima","year":"2018","journal-title":"J. Braz. Chem. Soc."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1016\/j.bmc.2013.12.039","article-title":"Direct synthesis of C3-mono-functionalized oxindoles from N-unprotected 2-oxindole and their antileishmanial activity","volume":"22","author":"Scala","year":"2014","journal-title":"Bioorganic Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"6281","DOI":"10.1128\/AAC.00352-16","article-title":"A novel spirooxindole derivative inhibits the growth of Leishmania donovani parasites both in vitro and in vivo by targeting type IB topoisomerase","volume":"60","author":"Saha","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1093\/protein\/9.11.1063","article-title":"An automated approach for clustering an ensemble of NMR-derived protein structures into conformationally related subfamilies","volume":"9","author":"Kelley","year":"1996","journal-title":"Protein Eng. Des. Sel."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1021\/ci8001952","article-title":"Using molecular docking, 3D-QSAR, and cluster analysis for screening structurally diverse data sets of pharmacological interest","volume":"48","author":"Cherkasov","year":"2008","journal-title":"J. Chem. Inf. Model."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1002\/minf.201000061","article-title":"Best Practices for QSAR Model Development, Validation, and Exploitation","volume":"29","author":"Tropsha","year":"2010","journal-title":"Mol. Inform."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"10509","DOI":"10.1021\/ja9718937","article-title":"Construction of 3D-QSAR models using the 4D-QSAR analysis formalism","volume":"119","author":"Hopfinger","year":"1997","journal-title":"J. Am. Chem. Soc."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1007\/s11030-011-9340-3","article-title":"4D-LQTA-QSAR and docking study on potent gram-negative specific LpxC inhibitors: A comparison to CoMFA modeling","volume":"16","author":"Ghasemi","year":"2012","journal-title":"Mol. Divers."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5959","DOI":"10.1021\/ja00226a005","article-title":"Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins","volume":"110","author":"Cramer","year":"1988","journal-title":"J. Am. Chem. Soc."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1021\/ci300039a","article-title":"A 4D structure-activity relationship model to predict HIV-1 integrase strand transfer inhibition using the LQTA-QSAR methodology","volume":"52","author":"Melo","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.4155\/fmc-2016-0093","article-title":"AutoQSAR: An automated machine learning tool for best-practice quantitative structure\u2013activity relationship modeling","volume":"8","author":"Dixon","year":"2016","journal-title":"Future Med. Chem."},{"key":"ref_20","unstructured":"Release, S. (2017). Maestro, Schr\u00f6dinger LLC. Version 3."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Medeiros, A.R., Ferreira, L.L., de Souza, M.L., de Oliveira Rezende, C., Espinoza-Ch\u00e1vez, R.M., Dias, L.C., and Andricopulo, A.D. (2021). Chemoinformatics Studies on a Series of Imidazoles as Cruzain Inhibitors. Biomolecules, 11.","DOI":"10.26226\/morressier.616e5c2462ba8657678b135c"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"De Souza, A.S., Ferreira, L.L., de Oliveira, A.S., and Andricopulo, A.D. (2019). Quantitative Structure-Activity Relationships for Structurally Diverse Chemotypes Having Anti-Trypanosoma cruzi Activity. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20112801"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.1021\/jm401411z","article-title":"Molecular similarity in medicinal chemistry: Miniperspective","volume":"57","author":"Maggiora","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1145\/1656274.1656280","article-title":"KNIME\u2014The Konstanz Information Miner: Version 2.0 and Beyond","volume":"11","author":"Berthold","year":"2009","journal-title":"SIGKDD Explor. Newsl."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1016\/j.jmgm.2008.01.002","article-title":"The importance of the domain of applicability in QSAR modeling","volume":"26","author":"Weaver","year":"2008","journal-title":"J. Mol. Graph. Model."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4791","DOI":"10.3390\/molecules17054791","article-title":"Comparison of different approaches to define the applicability domain of QSAR models","volume":"17","author":"Sahigara","year":"2012","journal-title":"Molecules"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1021\/ci900014f","article-title":"LQTA-QSAR: A new 4D-QSAR methodology","volume":"49","author":"Martins","year":"2009","journal-title":"J. Chem. Inf. Modeling"},{"key":"ref_28","unstructured":"Bekker, H., Berendsen, H., Dijkstra, E., Achterop, S., Vondrumen, R., Vanderspoel, D., Sijbers, A., Keegstra, H., and Renardus, M. (1993). Gromacs-a parallel computer for molecular-dynamics simulations. Physics Computing \u201992, World Scientific Publishing."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/0010-4655(95)00042-E","article-title":"GROMACS: A message-passing parallel molecular dynamics implementation","volume":"91","author":"Berendsen","year":"1995","journal-title":"Comput. Phys. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1002\/jcc.1078","article-title":"An improved GROMOS96 force field for aliphatic hydrocarbons in the condensed phase","volume":"22","author":"Schuler","year":"2001","journal-title":"J. Comput. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1007\/s00249-002-0269-4","article-title":"A consistent potential energy parameter set for lipids: Dipalmitoylphosphatidylcholine as a benchmark of the GROMOS96 45A3 force field","volume":"32","author":"Chandrasekhar","year":"2003","journal-title":"Eur. Biophys. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1103\/PhysRevLett.45.1196","article-title":"Crystal Structure and Pair Potentials: A Molecular-Dynamics Study","volume":"45","author":"Parrinello","year":"1980","journal-title":"Phys. Rev. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3684","DOI":"10.1063\/1.448118","article-title":"Molecular dynamics with coupling to an external bath","volume":"81","author":"Berendsen","year":"1984","journal-title":"J. Chem. Phys."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1002\/bkcs.11638","article-title":"PyQSAR: A fast QSAR modeling platform using machine learning and Jupyter notebook","volume":"40","author":"Kim","year":"2019","journal-title":"Bull. Korean Chem. Soc."},{"key":"ref_35","unstructured":"Schr\u00f6dinger, LLC (2016). The PyMOL Molecular Graphics System, Schr\u00f6dinger Inc.. Version 1.8."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/8898\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:06:40Z","timestamp":1760141200000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/16\/8898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,8,10]]},"references-count":35,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2022,8]]}},"alternative-id":["ijms23168898"],"URL":"https:\/\/doi.org\/10.3390\/ijms23168898","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,8,10]]}}}