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Reactivating SERCA2a improves cardiac function in heart failure models, making it a validated target and an attractive therapeutic approach for heart failure therapy. However, finding small\u2010molecule SERCA2a activators is challenging. In this study, we used a machine learning\u2010based virtual screening to identify SERCA2a activators among 57,423 natural products. The machine learning model identified ten structurally related natural products from <jats:italic>Zingiber officinale<\/jats:italic>, <jats:italic>Aframomum melegueta<\/jats:italic>, <jats:italic>Alpinia officinarum, Alpinia oxyphylla<\/jats:italic>, and <jats:italic>Capsicum<\/jats:italic> (chili peppers) as SERCA2a activators. Initial ATPase assays showed seven of these activate SERCA at low micromolar concentrations. Notably, two natural products, Yakuchinone A and Alpinoid D displayed robust concentration\u2010dependent responses in primary ATPase activity assays, efficient lipid bilayer binding and permeation in atomistic simulations, and enhanced intracellular Ca<jats:sup>2+<\/jats:sup> transport in adult mouse cardiac cells. While these natural products exert off\u2010target effects on Ca<jats:sup>2+<\/jats:sup> signaling, these compounds offer promising avenues for the design and optimization of lead compounds. In conclusion, this study increases the array of calcium pump effectors and provides new scaffolds for the development of novel SERCA2a activators as new therapies for heart failure.<\/jats:p>","DOI":"10.1002\/cmdc.202400913","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T22:28:53Z","timestamp":1737671333000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Machine Learning\u2010Driven Discovery of Structurally Related Natural Products as Activators of the Cardiac Calcium Pump SERCA2a"],"prefix":"10.1002","volume":"20","author":[{"given":"Carlos","family":"Cruz\u2010Cort\u00e9s","sequence":"first","affiliation":[{"name":"Center for Arrhythmia Research Department of Internal Medicine Division of Cardiovascular Medicine University of Michigan  Ann Arbor MI-48109 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eli","family":"Fern\u00e1ndez\u2010de Gortari","sequence":"additional","affiliation":[{"name":"International Iberian Nanotechnology Laboratory  Braga 4715-330 Portugal"},{"name":"Euskal Oxcitas Biotek SL  Calle Lutxana 11 \u2013 DCHA 48008 Bilbao Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodrigo","family":"Aguayo\u2010Ortiz","sequence":"additional","affiliation":[{"name":"Departamento de Farmacia Facultad de Qu\u00edmica Universidad Nacional Aut\u00f3noma de M\u00e9xico  Mexico City 04510 Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaroslava","family":"\u0160eflov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Cell and Molecular Physiology Loyola University Chicago  Maywood IL-60153 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Ard","sequence":"additional","affiliation":[{"name":"College of Pharmacy University of Michigan  Ann Arbor MI-48109 USA"},{"name":"Vahlteich Medicinal Chemistry Core University of Michigan  Ann Arbor MI-48109 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Clasby","sequence":"additional","affiliation":[{"name":"College of Pharmacy University of Michigan  Ann Arbor MI-48109 USA"},{"name":"Vahlteich Medicinal Chemistry Core University of Michigan  Ann Arbor MI-48109 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justus","family":"Anumonwo","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research Department of Internal Medicine Division of Cardiovascular Medicine University of Michigan  Ann Arbor MI-48109 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1006-6504","authenticated-orcid":false,"given":"L.","family":"Michel Espinoza\u2010Fonseca","sequence":"additional","affiliation":[{"name":"Center for Arrhythmia Research Department of Internal Medicine Division of Cardiovascular Medicine University of Michigan  Ann Arbor MI-48109 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,2,6]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2021.11.023"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2014.10.012"},{"key":"e_1_2_7_3_1","doi-asserted-by":"crossref","unstructured":"L. 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