{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T19:37:44Z","timestamp":1772480264469,"version":"3.50.1"},"reference-count":110,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T00:00:00Z","timestamp":1747958400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Bill and Melinda Gates Foundation","award":["AAS\/APTI2\/005"],"award-info":[{"award-number":["AAS\/APTI2\/005"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Objective: Falciparum malaria is a major global health concern, affecting more than half of the world\u2019s population and causing over half a million deaths annually. Red cell invasion is a crucial step in the parasite\u2019s life cycle, where the parasite invade human erythrocytes to sustain infection and ensure survival. Two parasite proteins, Apical Membrane Antigen 1 (AMA-1) and Rhoptry Neck Protein 2 (RON2), are involved in tight junction formation, which is an essential step in parasite invasion of the red blood cell. Targeting the AMA-1 and RON2 interaction with inhibitors halts the formation of the tight junction, thereby preventing parasite invasion, which is detrimental to parasite survival. This study leverages machine learning (ML) to predict potential small molecule inhibitors of the AMA-1\u2013RON2 interaction, providing putative antimalaria compounds for further chemotherapeutic exploration. Method: Data was retrieved from the PubChem database (AID 720542), comprising 364,447 inhibitors and non-inhibitors of the AMA-1\u2013RON2 interaction. The data was processed by computing Morgan fingerprints and divided into training and testing with an 80:20 ratio, and the classes in the training data were balanced using the Synthetic Minority Oversampling Technique. Five ML models developed comprised Random Forest (RF), Gradient Boost Machines (GBMs), CatBoost (CB), AdaBoost (AB) and Support Vector Machine (SVM). The performances of the models were evaluated using accuracy, F1 score, and receiver operating characteristic\u2014area under the curve (ROC-AUC) and validated using held-out data and a y-randomization test. An applicability domain analysis was carried out using the Tanimoto distance with a threshold set at 0.04 to ascertain the sample space where the models predict with confidence. Results: The GBMs model emerged as the best, achieving 89% accuracy and a ROC-AUC of 92%. CB and RF had accuracies of 88% and 87%, and ROC-AUC scores of 93% and 91%, respectively. Conclusions: Experimentally validated inhibitors of the AMA-1\u2013RON2 interaction could serve as starting blocks for the next-generation antimalarial drugs. The models were deployed as a web-based application, known as PLASMOpred.<\/jats:p>","DOI":"10.3390\/ph18060776","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T06:16:03Z","timestamp":1747980963000},"page":"776","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["PLASMOpred: A Machine Learning-Based Web Application for Predicting Antimalarial Small Molecules Targeting the Apical Membrane Antigen 1\u2013Rhoptry Neck Protein 2 Invasion Complex"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3354-1500","authenticated-orcid":false,"given":"Eugene","family":"Lamptey","sequence":"first","affiliation":[{"name":"West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, Ghana"},{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0844-8067","authenticated-orcid":false,"given":"Jessica","family":"Oparebea","sequence":"additional","affiliation":[{"name":"West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, Ghana"},{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabriel","family":"Anyaele","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Belinda","family":"Ofosu","sequence":"additional","affiliation":[{"name":"West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, Ghana"},{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-2720-9102","authenticated-orcid":false,"given":"George","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra P.O. Box LG 581, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick O.","family":"Sakyi","sequence":"additional","affiliation":[{"name":"Department of Chemistry, School of Physical and Mathematical Sciences, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 56, Ghana"},{"name":"Department of Chemical Sciences, School of Sciences, University of Energy and Natural Resources, Sunyani P.O. Box 214, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1484-9833","authenticated-orcid":false,"given":"Odame","family":"Agyapong","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8920-0708","authenticated-orcid":false,"given":"Dominic S. Y.","family":"Amuzu","sequence":"additional","affiliation":[{"name":"West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3822-7940","authenticated-orcid":false,"suffix":"III","given":"Whelton A.","family":"Miller","sequence":"additional","affiliation":[{"name":"Department of Medicine, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"},{"name":"Department of Molecular Pharmacology & Neuroscience, Loyola University Medical Center, Loyola University Chicago, Maywood, IL 60153, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1093-1517","authenticated-orcid":false,"given":"Samuel K.","family":"Kwofie","sequence":"additional","affiliation":[{"name":"West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, Ghana"},{"name":"Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 77, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2756-8427","authenticated-orcid":false,"given":"Henrietta Esi","family":"Mensah-Brown","sequence":"additional","affiliation":[{"name":"West African Center for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Legon, Accra P.O. Box LG 54, Ghana"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Munisi, D.Z., and Mathania, M.M. (2022). Adult Anopheles Mosquito Distribution at a Low and High Malaria Transmission Site in Tanzania. Biomed Res. 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