Abstract:
The development of small molecule myosin modulators has seen an increased effort in recent years due to their possible use in the treatment of cardiac and skeletal myopathies. Omecamtiv mecarbil (OM) is the first-in-class cardiac myotrope and the first to enter clinical trials. Its selectivity toward slow/beta-cardiac myosin lies at the heart of its function; however, little is known about the underlying reasons for selectivity to this isoform as opposed to other closely related ones such as fast-type skeletal myosins. In this work, we compared the structure and dynamics of the OM binding site in cardiac and in fasttype IIa skeletal myosin to identify possible reasons for OM selectivity. We found that the different shape, size, and composition of the binding pocket in skeletal myosin directly affects the binding mode and related affinity of OM, which is potentially a result of weaker interactions and less optimal molecular recognition. Moreover, we identified a side pocket adjacent to the OM binding site that shows increased accessibility in skeletal myosin compared with the cardiac isoform. These findings could pave the way to the development of skeletal-selective compounds that can target this region of the protein and potentially be used to treat congenital myopathies where muscle weakness is related to myosin loss of function.
摘要:
近年来,由于小分子肌球蛋白调节剂可能用于治疗心脏和骨骼肌病,因此其开发工作有所增加。Omecamtivmecarbil(OM)是一流的心脏肌力疗法,也是第一个进入临床试验的人。它对慢/β-心脏肌球蛋白的选择性在于其功能的核心;然而,与其他密切相关的亚型(例如快速型骨骼肌肌球蛋白)相比,对该亚型的选择性的根本原因知之甚少。在这项工作中,我们比较了心脏和fastIIa型骨骼肌肌球蛋白中OM结合位点的结构和动力学,以确定OM选择性的可能原因。我们发现不同的形状,尺寸,骨骼肌肌球蛋白结合袋的组成直接影响OM的结合模式和相关亲和力,这可能是较弱的相互作用和不太理想的分子识别的结果。此外,我们确定了与OM结合位点相邻的侧袋,与心脏同工型相比,骨骼肌肌球蛋白的可及性增加。这些发现可以为骨骼选择性化合物的发展铺平道路,这些化合物可以靶向蛋白质的该区域,并可能用于治疗先天性肌病,其中肌肉无力与肌球蛋白功能丧失有关。