SOD1
肌萎缩侧索硬化
化学
超氧化物歧化酶
对接(动物)
生物化学
立体化学
色氨酸
药物发现
生物物理学
氨基酸
氧化应激
医学
生物
病理
护理部
疾病
作者
R Manjula,Sruthi Unni,Gareth S. A. Wright,Srinivas Bharath M. M.,Balasundaram Padmanabhan
标识
DOI:10.1080/07391102.2018.1531787
摘要
Formation of Cu, Zn superoxide dismutase 1 (SOD1) protein inclusions within motor neurons is one of the principal characteristics of SOD1-related amyotrophic lateral sclerosis (ALS). A hypothesis as to the nature of SOD1 aggregation implicates oxidative damage to a solvent-exposed tryptophan as causative. Here, we chart the discovery of a phenanthridinone based compound (Lig9) from the NCI Diversity Set III by rational methods by in silico screening and crystallographic validation. The crystal structure of the complex with SOD1, refined to 2.5 Å, revealed that Lig9 binds the SOD1 β-barrel in the β-strand 2 and 3 region which is known to scaffold SOD1 fibrillation. The phenanthridinone moiety makes a substantial π-π interaction with Trp32 of SOD1. The compound possesses a significant binding affinity for SOD1 and inhibits oxidation of Trp32; a critical residue for SOD1 aggregation. Thus, Lig9 is a good candidate from which to develop a new library of SOD1 aggregation inhibitors through protection of Trp32 oxidation. Communicated by Ramaswamy H. Sarma.
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