Structural Motility, Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144, Paris, 75248, France.
Laboratoire de Physiologie, Ecologie et Environnement (P2E), UPRES EA 1207/USC INRAE-1328, UFR Sciences et Techniques, Université d'Orléans, Orléans, France.
Nat Commun. 2024 Jun 7;15(1):4885. doi: 10.1038/s41467-024-47587-9.
Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by β-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.
遗传性心肌病是全球常见的心脏疾病，在疾病晚期会导致心力衰竭和死亡。针对这些疾病最有前途的治疗方法是直接调节β-心肌球蛋白产生的力的小分子，β-心肌球蛋白是驱动心脏收缩的分子马达。Omecamtiv mecarbil 和 Mavacamten 是两种已完成 3 期临床试验的此类分子，抑制剂 Mavacamten 现已获得 FDA 批准。与 Mavacamten 不同，Omecamtiv mecarbil 作为心肌收缩力的激活剂。在这里，我们通过 X 射线晶体学揭示，这两种药物靶向相同的口袋并稳定预冲程结构状态，只有少数局部差异。全原子分子动力学模拟揭示了这些分子如何在马达变构中产生不同的影响，从而以相反的方式影响力的产生。总之，我们的研究结果为个性化医学目的的合理药物开发提供了框架。
