From in Silico Discovery to Intracellular Activity: Targeting JNK鈥揚rotein Interactions with Small Molecules
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- 作者：Tamer S. Kaoud ; Chunli Yan ; Shreya Mitra ; Chun-Chia Tseng ; Jiney Jose ; Juliana M. Taliaferro ; Maidina Tuohetahuntila ; Ashwini Devkota ; Rachel Sammons ; Jihyun Park ; Heekwang Park ; Yue Shi ; Jiyong Hong ; Pengyu Ren ; Kevin N. Dalby
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：September 13, 2012
- 年：2012
- 卷：3
- 期：9
- 页码：721-725
- 全文大小：332K
- 年卷期：v.3,no.9(September 13, 2012)
- ISSN：1948-5875
文摘
The JNK鈥揓IP1 interaction represents an attractive target for the selective inhibition of JNK-mediated signaling. We report a virtual screening (VS) workflow, based on a combination of three-dimensional shape and electrostatic similarity, to discover novel scaffolds for the development of non-ATP competitive inhibitors of JNK targeting the JNK鈥揓IP interaction. Of 352 (0.13%) compounds selected from the NCI Diversity Set, more than 22% registered as hits in a biochemical kinase assay. Several compounds discovered to inhibit JNK activity under standard kinase assay conditions also impeded JNK activity in HEK293 cells. These studies led to the discovery that the lignan (鈭?-zuonin A inhibits JNK鈥損rotein interactions with a selectivity of 100-fold over ERK2 and p38 MAPK伪. These results demonstrate the utility of a virtual screening protocol to identify novel scaffolds for highly selective, cell-permeable inhibitors of JNK鈥損rotein interactions.