Structure-based discovery of a novel non-peptidic small molecular inhibitor of caspase-3.
Structure-based discovery of a novel non-peptidic small molecular inhibitor of caspase-3.
复制标题
基于结构的 caspase-3 新型非肽小分子抑制剂的发现。
DOI：
10.1016/j.bmc.2008.03.046
复制
发表时间：
2008
影响因子：
3.5
通讯作者：
S. Tanuma
中科院分区：
文献类型：
--
作者：
J. Sakai;A. Yoshimori;Y. Nose;Akihiko Mizoroki;Naoyuki Okita;R. Takasawa;S. Tanuma
Ac-DNLD-CHO是一种新型的caspase-3特异性肽抑制剂，通过我们的计算策略合理设计。根据对接模式和定点诱变分析，这种特异性是由于NLD片段与caspase-3活性位点的特异性相互作用。在这里，我们使用从NLD的特定结合模式中获得的可靠药效团，从我们的化学文库中计算筛选caspase-3的非肽类小分子抑制剂。通过对筛选的候选化合物进行体外酶分析，我们发现了一种新的caspase-3特异性小分子抑制剂CS4566，它具有独特的支架结构。CS4566与caspase-3的结合模式与NLD，尤其是LD部分的结合模式相似。这代表了一种有希望的先导化合物，用于制造用于半胱天冬酶介导的疾病（如神经退行性疾病）的非肽类药物。
Ac-DNLD-CHO is a novel caspase-3 specific peptide inhibitor that was rationally designed by our computational strategy. The specificity was shown to be due to the specific interaction of NLD moiety with the active site of caspase-3 on the basis of docking mode and site-directed mutagenesis analyses. Here, we computationally screened non-peptidic small molecular inhibitors of caspase-3 from our chemical library using a reliable pharmacophore derived from the specific binding mode of NLD. Through in vitro enzyme assay of the screened candidate compounds, we discovered a novel caspase-3 specific small molecular inhibitor, CS4566, which has a unique scaffold structure. The binding mode of CS4566 to caspase-3 mimics that of NLD, especially LD moiety. This represents a promising lead compound for creating non-peptidic pharmaceuticals for caspase-mediated diseases, such as neurodegenerative disorders.
影响因子：
15.9
作者：
Cheng, Y;Deshmukh, M;Holtzman, DM
通讯作者：
Holtzman, DM
影响因子：
16
作者：
Srinivasula, SM;Ahmad, M;Alnemri, ES
通讯作者：
Alnemri, ES
影响因子：
56.9
作者：
Li, MW;Ona, VO;Friedlander, RM
通讯作者：
Friedlander, RM