Rush Thomas S, Grant J Andrew, Mosyak Lidia, Nicholls Anthony
Department of Chemical & Screening Sciences, Wyeth Research, 87 Cambridge Park Drive, Cambridge, MA 02140, USA.
J Med Chem. 2005 Mar 10;48(5):1489-95. doi: 10.1021/jm040163o.
In this paper, we describe the first prospective application of the shape-comparison program ROCS (Rapid Overlay of Chemical Structures) to find new scaffolds for small molecule inhibitors of the ZipA-FtsZ protein-protein interaction, a proposed antibacterial target. The shape comparisons are made relative to the crystallographically determined, bioactive conformation of a high-throughput screening (HTS) hit. The use of ROCS led to the identification of a set of novel, weakly binding inhibitors with scaffolds presenting synthetic opportunities to further optimize biological affinity and lacking development issues associated with the HTS lead. These ROCS-identified scaffolds would have been missed using other structural similarity approaches such as ISIS 2D fingerprints. X-ray crystallographic analysis of one of the new inhibitors bound to ZipA reveals that the shape comparison approach very accurately predicted the binding mode. These experimental results validate this use of ROCS for chemotype switching or "lead hopping" and suggest that it is of general interest for lead identification in drug discovery endeavors.
在本文中，我们描述了形状比较程序ROCS（化学结构快速叠加）首次前瞻性地应用于寻找ZipA-FtsZ蛋白-蛋白相互作用小分子抑制剂的新骨架，该相互作用是一个潜在的抗菌靶点。形状比较是相对于高通量筛选（HTS）命中化合物的晶体学确定的生物活性构象进行的。ROCS的使用导致鉴定出一组新型的弱结合抑制剂，其骨架提供了进一步优化生物亲和力的合成机会，并且不存在与HTS先导化合物相关的开发问题。使用其他结构相似性方法（如ISIS二维指纹）会遗漏这些由ROCS鉴定出的骨架。对一种与ZipA结合的新抑制剂进行的X射线晶体学分析表明，形状比较方法非常准确地预测了结合模式。这些实验结果验证了ROCS在化学型转换或“先导跳跃”中的这种应用，并表明它在药物发现工作中的先导物鉴定方面具有普遍意义。
