Sanders William J, Nienaber Vicki L, Lerner Claude G, McCall J Owen, Merrick Sean M, Swanson Susan J, Harlan John E, Stoll Vincent S, Stamper Geoffrey F, Betz Stephen F, Condroski Kevin R, Meadows Robert P, Severin Jean M, Walter Karl A, Magdalinos Peter, Jakob Clarissa G, Wagner Rolf, Beutel Bruce A
Infectious Disease Research, Abbott Laboratories, 200 Abbott Park Road, Abbott Park, Illinois 60064-6217, USA.
J Med Chem. 2004 Mar 25;47(7):1709-18. doi: 10.1021/jm030497y.
Potent inhibitors of 7,8-dihydroneopterin aldolase (DHNA; EC 4.1.2.25) have been discovered using CrystaLEAD X-ray crystallographic high-throughput screening followed by structure-directed optimization. Screening of a 10 000 compound random library provided several low affinity leads and their corresponding X-ray crystal structures bound to the enzyme. The presence of a common structural feature in each of the leads suggested a strategy for the construction of a directed library of approximately 1000 compounds that were screened for inhibitory activity in a traditional enzyme assay. Several lead compounds with IC(50) values of about 1 microM against DHNA were identified, and crystal structures of their enzyme-bound complexes were obtained by cocrystallization. Structure-directed optimization of one of the leads thus identified afforded potent inhibitors with submicromolar IC(50) values.
通过晶体先导X射线晶体学高通量筛选，随后进行结构导向优化，已发现7,8-二氢新蝶呤醛缩酶（DHNA；EC 4.1.2.25）的强效抑制剂。对一个包含10000种化合物的随机文库进行筛选，得到了几种低亲和力的先导化合物及其与该酶结合的相应X射线晶体结构。每种先导化合物中存在的共同结构特征提示了一种构建约1000种化合物的定向文库的策略，该文库在传统酶分析中进行了抑制活性筛选。鉴定出了几种对DHNA的IC(50)值约为1 microM的先导化合物，并通过共结晶获得了它们与酶结合复合物的晶体结构。对如此鉴定出的一种先导化合物进行结构导向优化，得到了IC(50)值为亚微摩尔级的强效抑制剂。
