Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction.
Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction.
复制标题
Omecamtiv mecarbil 和 Mavacamten 靶向相同的肌球蛋白袋，尽管对心脏收缩有拮抗作用。
DOI：
10.1101/2023.11.15.567213
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Houdusse,Anne
中科院分区：
文献类型：
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作者：
Auguin,Daniel;Robert-Paganin,Julien;Réty,Stéphane;Kikuti,Carlos;David,Amandine;Theumer,Gabriele;Schmidt,ArndtW;Knölker,Hans-Joachim;Houdusse,Anne
遗传性心肌病是世界范围内最常见的心脏病之一，在晚期导致心力衰竭和死亡。针对这些疾病最有希望的治疗方法是直接调节β-心肌肌球蛋白（驱动心脏收缩的分子马达）产生的力的小分子。其中两种对心肌收缩力产生拮抗作用的分子已完成临床3期试验：激活剂Omecamtiv Mecarbil和抑制剂Mavacamten。在这项工作中，我们通过X射线晶体学揭示了两种药物靶向相同的口袋并稳定中风前的结构状态，只有很少的局部差异。通过比较载脂蛋白形式或与Omecamtiv mecarbil或Mavacamten结合的β-心肌肌球蛋白，所有原子分子动力学模拟揭示了这些分子如何对运动的变构产生拮抗作用。总而言之，我们的研究结果提供了一个框架，合理的药物开发的目的，个性化医疗。
Inherited cardiomyopathies are amongst the most 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. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activator Omecamtiv mecarbil and the inhibitor Mavacamten. In this work, 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 atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing β-cardiac myosin in the apo form or bound to Omecamtiv mecarbil or Mavacamten. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.