Choi Jiwon, Govindaraj Rajiv Gandhi, Hyeon Jae Wook, Lee Kyungro, Ma SongLing, Kim Su Yeon, Lee Jeongmin, No Kyoung Tai
Bioinformatics and Molecular Design Research Center, Yonsei University, Seoul, Korea.
Department of Medicinal Chemistry, University of Minnesota, Minneapolis, MN, USA.
Chem Biol Drug Des. 2017 Jun;89(6):907-917. doi: 10.1111/cbdd.12916. Epub 2017 Feb 6.
Transition of a physiological folded prion (PrP ) into a pathogenic misfolded prion (PrP ) causes lethal neurodegenerative disorders and prion diseases. Antiprion compounds have been developed to prevent this conversion; however, their mechanism of action remains unclear. Recently, we reported two antiprion compounds, BMD29 and BMD35, identified by in silico and in vitro screening. In this study, we used extensive explicit-solvent molecular dynamics simulations to investigate ligand-binding inhibition by antiprion compounds in prion folding over misfolding behavior at acidic pH. The two antiprion compounds and the previously reported GN8 compound resulted in a remarkably stabilized intermediate by binding to the hotspot region of PrP , whereas free PrP and the inactive compound BMD01 destabilized the structure of PrP leading to the misfolded form. The results uncovered a secondary structural transition of free PrP and transition suppression by the antiprion compounds. One of the major misfolding processes in PrP , alternation of hydrophobic core residues, disruption of intramolecular interactions, and the increase in residue solvent exposure were significantly inhibited by both antiprion compounds. These findings provide insights into prion misfolding and inhibition by antiprion compounds.
生理性折叠朊病毒（PrP ）转变为致病性错误折叠朊病毒（PrP ）会引发致命的神经退行性疾病和朊病毒病。抗朊病毒化合物已被开发用于预防这种转变；然而，它们的作用机制仍不清楚。最近，我们报道了通过计算机模拟和体外筛选鉴定出的两种抗朊病毒化合物BMD29和BMD35。在本研究中，我们使用广泛的显式溶剂分子动力学模拟来研究抗朊病毒化合物在酸性pH条件下对朊病毒折叠而非错误折叠行为的配体结合抑制作用。这两种抗朊病毒化合物以及先前报道的GN8化合物通过与PrP 的热点区域结合导致一种显著稳定的中间体，而游离的PrP 和无活性化合物BMD01则使PrP 的结构不稳定，导致错误折叠形式。结果揭示了游离PrP 的二级结构转变以及抗朊病毒化合物对这种转变的抑制作用。两种抗朊病毒化合物均显著抑制了PrP 中主要的错误折叠过程之一，即疏水核心残基的交替、分子内相互作用的破坏以及残基溶剂暴露的增加。这些发现为朊病毒错误折叠以及抗朊病毒化合物的抑制作用提供了见解。
