School of Chemistry, University of Nottingham, Nottingham NG7 2RD, U.K.
J Chem Inf Model. 2024 Oct 14;64(19):7687-7697. doi: 10.1021/acs.jcim.4c01379. Epub 2024 Sep 12.
Myotonic dystrophy type I (DM1) is the most common form of adult muscular dystrophy and is a severe condition with no treatment currently available. Recently, small-molecule ligands have been developed as targeted covalent inhibitors that have some selectivity for and covalently inhibit cyclin-dependent kinase 12 (CDK12). CDK12 is involved in the transcription of elongated RNA sections that results in the DM1 condition. The covalent bond is achieved after nucleophilic addition to a Michael acceptor warhead. Previous studies of the conformational preferences of thio-Michael additions have focused on characterizing the reaction profile based on the distance between the sulfur and β-carbon atoms. Rotamerism, however, has not been investigated extensively. Here, we use high-level quantum chemistry calculations, up to coupled cluster with single, double, and perturbative triple excitations [CCSD(T)], to characterize the nucleophilic addition of an archetypal nucleophile, methanethiolate, to various nitrogen-containing Michael acceptors which are representative of the small-molecule covalent inhibitors. By investigating the structural, energetic, and electronic properties of the resulting enolates, as well as their reaction profiles, we show that synclinal additions are generally energetically favored over other additions due to the greater magnitude of attractive noncovalent interactions permitted by the conformation. The calculated transition states associated with the addition process indicate that synclinal addition proceeds via lower energetic barriers than antiperiplanar addition and is the preferred reaction pathway.
Ⅰ型肌强直性营养不良（DM1）是最常见的成人肌肉营养不良形式，是一种严重的疾病，目前尚无治疗方法。最近，小分子配体已被开发为靶向共价抑制剂，对细胞周期蛋白依赖性激酶 12（CDK12）具有一定的选择性和共价抑制作用。CDK12 参与伸长 RNA 片段的转录，导致 DM1 状况。共价键是通过亲核加成到迈克尔受体弹头来实现的。以前对硫代迈克尔加成的构象偏好的研究主要集中在根据硫原子和β碳原子之间的距离来描述反应概况。然而，旋转异构体尚未得到广泛研究。在这里，我们使用高级量子化学计算，最高可达单、双和微扰三重激发[CCSD（T）]，来描述原型亲核试剂甲硫醇盐对各种含氮迈克尔受体的亲核加成，这些受体代表小分子共价抑制剂。通过研究生成的烯醇化物的结构、能量和电子性质及其反应概况，我们表明，由于构象允许更大的吸引力非共价相互作用，顺式加成通常在能量上优于其他加成。与加成过程相关的计算过渡态表明，顺式加成比反式加成具有更低的能量障碍，是首选的反应途径。
