Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Barcelona 08193, Spain.
J Med Chem. 2022 Nov 10;65(21):14673-14691. doi: 10.1021/acs.jmedchem.2c01195. Epub 2022 Oct 28.
Transthyretin amyloidosis (ATTR) is a group of fatal diseases described by the misfolding and amyloid deposition of transthyretin (TTR). Discovering small molecules that bind and stabilize the TTR tetramer, preventing its dissociation and subsequent aggregation, is a therapeutic strategy for these pathologies. Departing from the crystal structure of TTR in complex with tolcapone, a potent binder in clinical trials for ATTR, we combined rational design and molecular dynamics (MD) simulations to generate a series of novel halogenated kinetic stabilizers. Among them, displays one of the highest affinities for TTR described so far. The TTR/ crystal structure confirmed the formation of unprecedented protein-ligand contacts, as predicted by MD simulations, leading to an enhanced tetramer stability both and in whole serum. We demonstrate that MD-assisted design of TTR ligands constitutes a new avenue for discovering molecules that, like , hold the potential to become highly potent drugs to treat ATTR.
转甲状腺素淀粉样变性（ATTR）是一组由转甲状腺素（TTR）错误折叠和淀粉样沉积引起的致命疾病。发现与 TTR 四聚体结合并稳定其的小分子，防止其解离和随后的聚集，是这些病理的一种治疗策略。从与托卡朋（一种用于 ATTR 的临床试验中的有效结合物）结合的 TTR 晶体结构出发，我们结合了合理设计和分子动力学（MD）模拟，生成了一系列新型卤代动力学稳定剂。其中， 表现出迄今为止描述的对 TTR 具有最高亲和力之一。TTR/ 晶体结构证实了前所未有的蛋白质-配体接触的形成，正如 MD 模拟所预测的那样，导致四聚体稳定性增强， 和在整个血清中均如此。我们证明，TTR 配体的 MD 辅助设计为发现像 这样的分子提供了一条新途径，这些分子有可能成为治疗 ATTR 的高效药物。
