Improving binding specificity of pharmacological chaperones that target mutant superoxide dismutase-1 linked to familial amyotrophic lateral sclerosis using computational methods.
Improving binding specificity of pharmacological chaperones that target mutant superoxide dismutase-1 linked to familial amyotrophic lateral sclerosis using computational methods.
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DOI：
10.1021/jm901062p
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发表时间：
2010-04-08
影响因子：
7.3
通讯作者：
Ray SS
中科院分区：
文献类型：
--
作者：
Nowak RJ;Cuny GD;Choi S;Lansbury PT;Ray SS
我们最近描述了一组从计算机筛选中获得的类药物分子，它们可以稳定与家族性肌萎缩侧索硬化症 (ALS) 相关的突变型超氧化物歧化酶-1 (SOD-1)，防止其解折叠和聚集，但在血浆存在的情况下，对 SOD-1 的结合特异性较差。基于限制对接计算和二聚体界面关键残基的定点诱变，提出了这些分子结合的合理但不是决定性的模型。从这些实验中获得的一组氢键约束用于指导二聚体界面周围化合物库的对接计算。预测了一系列化学上不相关的命中，并通过实验测试了它们阻止聚集的能力。至少有六种新分子在血浆存在的情况下表现出与 SOD-1 的高度结合特异性。这些分子代表了一类新的分子，可进一步开发为临床候选药物。
We recently described a set of drug-like molecules obtained from an in silico screen that stabilize mutant superoxide dismutase-1 (SOD-1) linked to familial amyotrophic lateral sclerosis (ALS) against unfolding and aggregation but exhibited poor binding specificity towards SOD-1 in presence of blood plasma. A reasonable, but not a conclusive model for the binding of these molecules, was proposed based on restricted docking calculations and site-directed mutagenesis of key residues at the dimer interface. A set of hydrogen bonding constraints obtained from these experiments were used to guide docking calculations with compound library around the dimer interface. A series of chemically unrelated hits were predicted, which were experimentally tested for their ability to block aggregation. At least six of the new molecules exhibited high specificity of binding towards SOD-1 in presence of blood plasma. These molecules represent a new class of molecules for further development into clinical candidates.
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影响因子：
7.3
作者：
Johnson SM;Connelly S;Wilson IA;Kelly JW
通讯作者：
Kelly JW
影响因子：
4.4
作者：
Jia, Li-Yun;Gong, Bo;Yam, Gary Hin-Fai
通讯作者：
Yam, Gary Hin-Fai
影响因子：
1.6
作者：
Dobson, CM
通讯作者：
Dobson, CM
影响因子：
7.2
作者：
Kanki, Keita;Kawamura, Takeshi;Watanabe, Yoshifumi
通讯作者：
Watanabe, Yoshifumi
DOI：
10.1038/nsb935
发表时间：
2003-06-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Elam, JS;Taylor, AB;Hart, PJ
通讯作者：
Hart, PJ