Small Molecule Discovery Center, Sandler Center for Basic Research in Parasitic Diseases, and Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 4th Street, San Francisco, CA 94158, USA.
J Med Chem. 2009 Aug 27;52(16):5005-8. doi: 10.1021/jm9009229.
A docking screen identified reversible, noncovalent inhibitors (e.g., 1) of the parasite cysteine protease cruzain. Chemical optimization of 1 led to a series of oxadiazoles possessing interpretable SAR and potencies as much as 500-fold greater than 1. Detailed investigation of the SAR series subsequently revealed that many members of the oxadiazole class (and surprisingly also 1) act via divergent modes of inhibition (competitive or via colloidal aggregation) depending on the assay conditions employed.
对接筛选鉴定出寄生虫半胱氨酸蛋白酶 cruzain 的可逆非共价抑制剂（如化合物 1）。对化合物 1 进行化学优化得到一系列噁二唑类化合物，其具有可解释的 SAR 和高达 500 倍于化合物 1 的效力。对 SAR 系列的进一步研究表明，噁二唑类化合物的许多成员（以及令人惊讶的是，化合物 1）根据所使用的测定条件，通过不同的抑制模式（竞争性或胶态聚集）发挥作用。
