PDF(Pubmed)
Abstract：
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.
摘要：
遗传性心肌病是全球常见的心脏病,在晚期导致心力衰竭和死亡。这些疾病最有希望的治疗方法是小分子直接调节β-心肌肌球蛋白产生的力，分子马达驱动心脏收缩。Omecamtivmecarbil和Mavacanten是完成3期临床试验的两个这样的分子，抑制剂Mavacamten现已获得FDA批准。与Mavacamten相比,Omecamtivmecarbil充当心脏收缩力的激活剂。这里,我们通过X射线晶体学揭示了两种药物靶向同一个口袋，并稳定了中风前的结构状态，只有很少的地方差异。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体化用药的合理药物开发提供了框架.
