1. Academic Validation
  2. Machine Learning-Driven Discovery of Structurally Related Natural Products as Activators of the Cardiac Calcium Pump SERCA2a

Machine Learning-Driven Discovery of Structurally Related Natural Products as Activators of the Cardiac Calcium Pump SERCA2a

  • ChemMedChem. 2025 Jan 23:e202400913. doi: 10.1002/cmdc.202400913.
Carlos Cruz-Cortés 1 Eli Fernández-de Gortari 2 3 Rodrigo Aguayo-Ortiz 4 Jaroslava Šeflová 5 Adam Ard 6 7 Martin Clasby 6 7 Justus Anumonwo 1 L Michel Espinoza-Fonseca 1
Affiliations

Affiliations

  • 1 Center for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI-48109, USA.
  • 2 International Iberian Nanotechnology Laboratory, Braga, 4715-330, Portugal.
  • 3 Euskal Oxcitas Biotek SL, Calle Lutxana 11 - DCHA, 48008, Bilbao, Spain.
  • 4 Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, 04510, Mexico.
  • 5 Department of Cell and Molecular Physiology, Loyola University Chicago, Maywood, IL-60153, USA.
  • 6 College of Pharmacy, University of Michigan, Ann Arbor, MI-48109, USA.
  • 7 Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI-48109, USA.
Abstract

A key molecular dysfunction in heart failure is the reduced activity of the cardiac sarcoplasmic reticulum CA2+-ATPase (SERCA2a) in cardiac muscle cells. 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-molecule SERCA2a activators is challenging. In this study, we used a machine learning-based virtual screening to identify SERCA2a activators among 57,423 Natural Products. The machine learning model identified ten structurally related Natural Products from Zingiber officinale, Aframomum melegueta, Alpinia officinarum, Alpinia oxyphylla, and Capsicum (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-dependent responses in primary ATPase activity assays, efficient lipid bilayer binding and permeation in atomistic simulations, and enhanced intracellular CA2+ transport in adult mouse cardiac cells. While these Natural Products exert off-target effects on CA2+ 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.

Keywords

SERCA2a; cardiac calcium pump; heart failure; machine learning; small-molecule activator; small-molecule screening.

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