Rational Design of 4-Aryl-1,2,3-Triazoles for Indoleamine 2,3-Dioxygenase 1 Inhibition
详细信息 查看全文
- 作者：Ute F. R枚hrig ; Somi Reddy Majjigapu ; Aur茅lien Grosdidier ; Sylvian Bron ; Vincent Stroobant ; Luc Pilotte ; Didier Colau ; Pierre Vogel ; Beno卯t J. Van den Eynde ; Vincent Zoete ; Olivier Michielin
- 刊名：Journal of Medicinal Chemistry
- 出版年：2012
- 出版时间：June 14, 2012
- 年：2012
- 卷：55
- 期：11
- 页码：5270-5290
- 全文大小：899K
- 年卷期：v.55,no.11(June 14, 2012)
- ISSN：1520-4804
文摘
Indoleamine 2,3-dioxygenase 1 (IDO1) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. Starting from the scaffold of our previously discovered IDO1 inhibitor 4-phenyl-1,2,3-triazole, we used computational structure-based methods to design more potent ligands. This approach yielded highly efficient low molecular weight inhibitors, the most active being of nanomolar potency both in an enzymatic and in a cellular assay, while showing no cellular toxicity and a high selectivity for IDO1 over tryptophan 2,3-dioxygenase (TDO). A quantitative structure鈥揳ctivity relationship based on the electrostatic ligand鈥損rotein interactions in the docked binding modes and on the quantum chemically derived charges of the triazole ring demonstrated a good explanatory power for the observed activities.