{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T14:09:11Z","timestamp":1782914951660,"version":"3.54.5"},"reference-count":43,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,15]],"date-time":"2026-02-15T00:00:00Z","timestamp":1771113600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"USFQ-Collaboration","award":["41984"],"award-info":[{"award-number":["41984"]}]},{"DOI":"10.13039\/501100004245","name":"Universidad del Norte, Colombia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004245","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The emergence of drug-resistant strains of Plasmodium falciparum continues to challenge global malaria control efforts, underscoring the urgent need for novel therapeutic strategies. In this study, we present an integrative computational framework that combines ensemble machine learning, molecular docking, and molecular dynamics simulations to predict and characterize the antimalarial activity of compounds from the Malaria Box database. Initially, topographical and quantum mechanical descriptors were used to construct regression models for predicting pEC50 values, but due to the limited predictive performance in the global regression, a classification strategy was adopted, categorizing compounds into \u201cactive\u201d and \u201cvery active\u201d classes. The best ensemble classifier achieved robust performance (Acc10-fold = 0.738, Accext = 0.675), with good sensitivity and specificity over individual models. Subsequent regression modeling within each class yielded high predictive accuracy, with ensemble models reaching Q210-fold values of 0.810 and 0.793 for the very active and active classes, respectively. To explore potential mechanisms of action, molecular docking was performed against P. falciparum Cytochrome B, revealing strong binding affinities for most compounds, particularly those forming \u03c0\u2013\u03c0 stacking and hydrogen bonds with Glu272. Molecular dynamics simulations over 200 ns confirmed the stability of several ligand\u2013protein complexes, including unexpected behavior from compound M31, which demonstrated stable binding despite poor docking scores, suggesting a possible competitive inhibition mechanism. Binding free energy calculations further validated these findings, highlighting several promising candidates for future experimental evaluation. This integrative approach offers a powerful platform for accelerating antimalarial drug discovery by combining predictive modeling with mechanistic insights.<\/jats:p>","DOI":"10.3390\/ijms27041875","type":"journal-article","created":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T10:14:32Z","timestamp":1771236872000},"page":"1875","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Hybrid Computational Framework Integrating Ensemble Learning, Molecular Docking, and Dynamics for Predicting Antimalarial Efficacy of Malaria Box Compounds"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8189-148X","authenticated-orcid":false,"given":"Mart\u00edn","family":"Moreno","sequence":"first","affiliation":[{"name":"Grupo de Qu\u00edmica Computacional y Te\u00f3rica (QCT-USFQ), Departamento de Ingenier\u00eda Qu\u00edmica, Universidad San Francisco de Quito USFQ, Diego de Robles y V\u00eda Interoce\u00e1nica, Quito 170901, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebasti\u00e1n A.","family":"Cuesta","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Computacional y Te\u00f3rica (QCT-USFQ), Departamento de Ingenier\u00eda Qu\u00edmica, Universidad San Francisco de Quito USFQ, Diego de Robles y V\u00eda Interoce\u00e1nica, Quito 170901, Ecuador"},{"name":"Department of Chemistry, Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester M1 7DN, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6128-9504","authenticated-orcid":false,"given":"Jos\u00e9 R.","family":"Mora","sequence":"additional","affiliation":[{"name":"Grupo de Qu\u00edmica Computacional y Te\u00f3rica (QCT-USFQ), Departamento de Ingenier\u00eda Qu\u00edmica, Universidad San Francisco de Quito USFQ, Diego de Robles y V\u00eda Interoce\u00e1nica, Quito 170901, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7503-1528","authenticated-orcid":false,"given":"Edgar A.","family":"M\u00e1rquez Brazon","sequence":"additional","affiliation":[{"name":"Grupo de Investigaciones en Qu\u00edmica y Biolog\u00eda, Departamento de Qu\u00edmica y Biolog\u00eda, Facultad de Ciencias B\u00e1sicas, Universidad del Norte, Carrera 51B, Km 5, v\u00eda Puerto Colombia, Barranquilla 081007, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6177-7919","authenticated-orcid":false,"given":"Jos\u00e9 L.","family":"Paz","sequence":"additional","affiliation":[{"name":"Departamento Acad\u00e9mico de Qu\u00edmica Inorg\u00e1nica, Facultad de Qu\u00edmica e Ingenier\u00eda Qu\u00edmica, Universidad Nacional Mayor de San Marcos, Lima 15081, Peru"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9908-2418","authenticated-orcid":false,"given":"Guillermin","family":"Ag\u00fcero-Chapin","sequence":"additional","affiliation":[{"name":"CIIMAR\/CIMAR LA, Interdisciplinary Centre of Marine and Environmental Research, University of Porto, Terminal de Cruzeiros do Porto de Leix\u00f5es, Av. General Norton de Matos s\/n, 4450-208 Matosinhos, Portugal"},{"name":"Department of Biology, Faculty of Sciences, University of Porto, Rua do Campo Alegre 1021, 4169-007 Porto, Portugal"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3166-745X","authenticated-orcid":false,"given":"Noel","family":"P\u00e9rez-P\u00e9rez","sequence":"additional","affiliation":[{"name":"Colegio de Ciencias e Ingenier\u00edas \u201cEl Polit\u00e9cnico\u201d, Universidad San Francisco de Quito USFQ, Quito 170157, Ecuador"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3962-7658","authenticated-orcid":false,"given":"C\u00e9sar R.","family":"Garc\u00eda-Jacas","sequence":"additional","affiliation":[{"name":"Investigador por M\u00e9xico, Secretar\u00eda de Ciencia, Humanidades, Tecnolog\u00eda e Innovaci\u00f3n (Secihti), Ciudad de M\u00e9xico 03940, Mexico"},{"name":"Tecnol\u00f3gico Nacional de M\u00e9xico, Instituto Tecnol\u00f3gico de M\u00e9rida, Unidad de Posgrado e Investigaci\u00f3n, Av. 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