Cruz-Cortés Carlos, Fernández-de Gortari Eli, Aguayo-Ortiz Rodrigo, Šeflová Jaroslava, Ard Adam, Clasby Martin, Anumonwo Justus, Michel Espinoza-Fonseca L
Center for Arrhythmia Research, Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI-48109, USA.
International Iberian Nanotechnology Laboratory, Braga, 4715-330, Portugal.
ChemMedChem. 2025 May 5;20(9):e202400913. doi: 10.1002/cmdc.202400913. Epub 2025 Feb 6.
A key molecular dysfunction in heart failure is the reduced activity of the cardiac sarcoplasmic reticulum Ca-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 Ca transport in adult mouse cardiac cells. While these natural products exert off-target effects on Ca 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.
心力衰竭的一个关键分子功能障碍是心肌细胞中心脏肌浆网Ca - ATP酶（SERCA2a）的活性降低。在心力衰竭模型中重新激活SERCA2a可改善心脏功能，使其成为一个经过验证的靶点以及心力衰竭治疗中一种有吸引力的治疗方法。然而，寻找小分子SERCA2a激活剂具有挑战性。在本研究中，我们使用基于机器学习的虚拟筛选方法，在57423种天然产物中鉴定SERCA2a激活剂。该机器学习模型从姜、非洲豆蔻、高良姜、益智和辣椒中鉴定出十种结构相关的天然产物作为SERCA2a激活剂。初步的ATP酶分析表明，其中七种在低微摩尔浓度下可激活SERCA。值得注意的是，两种天然产物，矢车菊素A和山姜素D在初级ATP酶活性分析中表现出强烈的浓度依赖性反应，在原子模拟中具有有效的脂质双层结合和渗透能力，并增强了成年小鼠心脏细胞内的钙转运。虽然这些天然产物对钙信号传导有脱靶效应，但这些化合物为先导化合物的设计和优化提供了有前景的途径。总之，本研究增加了钙泵效应物的种类，并为开发新型SERCA2a激活剂作为心力衰竭的新疗法提供了新的支架。
