Abad Marta C, Gibbs Alan C, Zhang Xuqing
Structural Biology and Medicinal Chemistry, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Spring House, Pennsylvania, USA.
Methods Enzymol. 2011;493:487-508. doi: 10.1016/B978-0-12-381274-2.00019-4.
We describe here a method using protein crystallography as the sole detection tool for fragment-based lead discovery. The methodology consists of iterative design, synthesis, and X-ray crystallographic screening of three libraries of compounds. Target-specific compound design, by way of active site electron density in the presence of a bound fragment hit and the intentional lack of solution activity bias form the basis of our approach. We provide an example of this alternative fragment-based drug design (FBDD) method, detailing results from a campaign using ketohexokinase to generate a unique lead series with promising drug-like properties.
我们在此描述一种将蛋白质晶体学作为基于片段的先导化合物发现的唯一检测工具的方法。该方法包括对三个化合物库进行迭代设计、合成和X射线晶体学筛选。通过结合片段命中时的活性位点电子密度以及有意缺乏溶液活性偏差来进行目标特异性化合物设计，构成了我们方法的基础。我们提供了这种基于片段的药物设计（FBDD）替代方法的一个例子，详细介绍了使用酮己糖激酶开展的一项研究的结果，该研究产生了具有有望的类药物性质的独特先导化合物系列。
