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Dual modulation of these proteins represents an attractive multitarget strategy for central nervous system drug discovery. In this study, we focused on indole\/oxindole-based scaffolds, including indolamide and oxindole cores with piperazine motifs (often N-aryl piperazines), as a working hypothesis for multitarget MAO-B\/Sig-1R modulation. A ligand-based machine learning approach was applied to build robust quantitative structure\u2013activity relationship (QSAR) classifiers capable of identifying potential modulators of both targets. Using curated ChEMBL data sets, support vector machine models were trained with molecular descriptors selected via L1 regularization and forward feature selection. The final models achieved strong predictive performance (\u03ba &amp;gt; 0.78; accuracy &amp;gt;88%) and revealed key structural determinants of activity, including aromatic bridging\/planarity, polarizability-related terms, and complementary donor\u2013acceptor patterns. Virtual screening of 147 natural compounds using the developed QSAR models, followed by applicability domain filtering, identified 11 compounds with predicted dual-target potential. Subsequent docking-based analysis prioritized four compounds with plausible predicted binding modes at both targets, while molecular dynamics simulations (150 ns) supported the short-time scale stability of 2 selected protein\u2013ligand complexes. Overall, this work establishes general SAR principles for dual MAO-B\/Sig-1R modulation and highlights how descriptor-driven modeling can inform molecular design and the prioritization of compounds for synthesis in multitarget medicinal chemistry programs.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c00379","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T16:30:38Z","timestamp":1783441838000},"page":"7889-7899","source":"Crossref","is-referenced-by-count":0,"title":["Machine Learning-Driven\nDiscovery of Indole\/Oxoindole\u2013Piperazine\nScaffolds as Dual MAO-B\/Sig-1R Ligands for Neurodegenerative Disorders"],"prefix":"10.1021","volume":"66","author":[{"given":"Ulisses Candido","family":"da Silva","sequence":"first","affiliation":[{"name":"Federal University of Alfenas (UNIFAL) , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-00"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9723-0528","authenticated-orcid":true,"given":"Miller Santos","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas (UNIFAL) , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-00"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo Borba","family":"Alves","sequence":"additional","affiliation":[{"name":"Federal University of Sergipe (UFS) , , , ,","place":["Sa\u0303o Cristo\u0301va\u0303o, Sergipe, Brazil, 49107-230"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vale\u0301ria Vieira Moura","family":"Paixa\u0303o","sequence":"additional","affiliation":[{"name":"Federal University of Sergipe (UFS) , , , ,","place":["Sa\u0303o Cristo\u0301va\u0303o, Sergipe, Brazil, 49107-230"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Igor Rodrigues","family":"Lapa","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas (UNIFAL) , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-00"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Micaela M. Barbosa","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas (UNIFAL) , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-00"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo Pereira","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"State University of Campinas (UNICAMP) , , , ,","place":["Campinas, Sa\u0303o Paulo, Brazil, 13083-871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanda Pereira","family":"Almeida","sequence":"additional","affiliation":[{"name":"State University of Campinas (UNICAMP) , , , ,","place":["Campinas, Sa\u0303o Paulo, Brazil, 13083-871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisi Gomes","family":"Soares","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas (UNIFAL) , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-00"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela A.","family":"Chagas-Paula","sequence":"additional","affiliation":[{"name":"Federal University of Juiz de Fora , , , ,","place":["Juizde Fora, Minas Gerais, Brazil, 36036-900"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albert","family":"Katchborian-Neto","sequence":"additional","affiliation":[{"name":"Federal University of Sa\u0303o Carlos (UFSCAR) , , , ,","place":["Sa\u0303o Carlos, Sa\u0303o Paulo, Brazil, 13565-905"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago Branquinho","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Federal University of Sergipe (UFS) , , , ,","place":["Sa\u0303o Cristo\u0301va\u0303o, Sergipe, Brazil, 49107-230"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9129-4734","authenticated-orcid":true,"given":"Danielle Ferreira","family":"Dias","sequence":"additional","affiliation":[{"name":"Federal University of Alfenas (UNIFAL) , , , ,","place":["Alfenas, Minas Gerais, Brazil, 37130-00"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"issue":"21","key":"2026072709082229900_cit1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms232112958","article-title":"Neurodegenerative Diseases: Can Caffeine Be a Powerful\nAlly to Weaken Neuroinflammation?","volume":"23","author":"Ruggiero","year":"2022","journal-title":"Int. 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Mol.\nStruct."},{"issue":"42","key":"2026072709082229900_cit20","doi-asserted-by":"publisher","first-page":"54603","DOI":"10.1007\/s11356-024-34800-x","article-title":"A Novel Procedure for Selection of Molecular Descriptors:\nQSAR Model for Mutagenicity of Nitroaromatic Compounds","volume":"31","author":"Stankovic","year":"2024","journal-title":"Environ. Sci. Pollut. Res."},{"issue":"8","key":"2026072709082229900_cit21","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1080\/1062936X.2020.1782467","article-title":"Quantitative Structure-Activity\nRelationship Model for Classifying the Diverse Series of Antifungal\nAgents Using Ratio Weighted Penalized Logistic Regression","volume":"31","author":"Alharthi","year":"2020","journal-title":"SAR QSAR Environ. 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