Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening.
Small molecule correctors of F508del-CFTR discovered by structure-based virtual screening.
复制标题
DOI：
10.1007/s10822-010-9390-0
复制
发表时间：
2010-12
影响因子：
3.5
通讯作者：
Senderowitz, Hanoch
中科院分区：
文献类型：
--
作者：
Kalid, Ori;Mense, Martin;Fischman, Sharon;Shitrit, Alina;Bihler, Hermann;Ben-Zeev, Efrat;Schutz, Nili;Pedemonte, Nicoletta;Thomas, Philip J.;Bridges, Robert J.;Wetmore, Diana R.;Marantz, Yael;Senderowitz, Hanoch
关键词：
F508 del-CFTR的折叠校正剂通过利用CFTR的同源模型的基于计算机结构的筛选而发现。对CFTR的细胞内区段进行建模，并在结构域间界面处鉴定出三个空腔：（1）两个核苷酸结合结构域（NBD）之间的界面;（2）在F508缺失区域中NBD 1与细胞内环（ICL）4之间的界面;（3）NBD 1：2：ICL 1：2：4之间的多结构域界面。我们假设在这些界面结合的化合物可以改善蛋白质的稳定性，潜在地影响折叠产率或表面稳定性。在推定的结合位点进行了基于计算机结构的筛选，并在功能测定中测试了来自所有三个位点的总共496种候选化合物。共有15个化合物，代表不同的化学型，被确定为F508 del折叠校正。这对应于3%的命中率，比在相应的高通量筛选活动中获得的命中率高10倍。相同的结合位点也产生增效剂，最值得注意的是，具有双重校正剂-增效剂活性的化合物（双重作用）。具有两种活性类型的化合物可以证明是比纯校正剂或纯增效剂更好的CF治疗剂开发的先导物。据我们所知，这是第一个基于结构发现CFTR调节剂的报告。
Folding correctors of F508del-CFTR were discovered by in silico structure-based screening utilizing homology models of CFTR. The intracellular segment of CFTR was modeled and three cavities were identified at inter-domain interfaces: (1) Interface between the two Nucleotide Binding Domains (NBDs); (2) Interface between NBD1 and Intracellular Loop (ICL) 4, in the region of the F508 deletion; (3) multi-domain interface between NBD1:2:ICL1:2:4. We hypothesized that compounds binding at these interfaces may improve the stability of the protein, potentially affecting the folding yield or surface stability. In silico structure-based screening was performed at the putative binding-sites and a total of 496 candidate compounds from all three sites were tested in functional assays. A total of 15 compounds, representing diverse chemotypes, were identified as F508del folding correctors. This corresponds to a 3% hit rate, ∼tenfold higher than hit rates obtained in corresponding high-throughput screening campaigns. The same binding sites also yielded potentiators and, most notably, compounds with a dual corrector-potentiator activity (dual-acting). Compounds harboring both activity types may prove to be better leads for the development of CF therapeutics than either pure correctors or pure potentiators. To the best of our knowledge this is the first report of structure-based discovery of CFTR modulators.
登录
查看更多内容
影响因子：
5.6
作者：
JONES, G;WILLETT, P;GLEN, RC
通讯作者：
GLEN, RC
影响因子：
5.6
作者：
Halgren, Thomas A.
通讯作者：
Halgren, Thomas A.
DOI：
10.1021/ci980335o
发表时间：
1999-07-01
期刊：
JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES
影响因子：
--
作者：
Filimonov, D;Poroikov, V;Gloriozova, T
通讯作者：
Gloriozova, T
影响因子：
2.9
作者：
Huang, Sheng-You;Bolser, Diana;Liu, Hao-Yang;Hwang, Tzyh-Chang;Zou, Xiaoqin
通讯作者：
Zou, Xiaoqin
影响因子：
64.8
作者：
Dawson, Roger J. P.;Locher, Kaspar P.
通讯作者：
Locher, Kaspar P.