Noeske Tobias, Trifanova Dina, Kauss Valerjans, Renner Steffen, Parsons Christopher G, Schneider Gisbert, Weil Tanja
Merz Pharmaceuticals GmbH, Altenhöfer Allee 3, D-60438 Frankfurt, Germany.
Bioorg Med Chem. 2009 Aug 1;17(15):5708-15. doi: 10.1016/j.bmc.2009.05.072. Epub 2009 Jun 23.
We report the identification of novel potent and selective metabotropic glutamate receptor 1 (mGluR1) antagonists by virtual screening and subsequent hit optimization. For ligand-based virtual screening, molecules were represented by a topological pharmacophore descriptor (CATS-2D) and clustered by a self-organizing map (SOM). The most promising compounds were tested in mGluR1 functional and binding assays. We identified a potent chemotype exhibiting selective antagonistic activity at mGluR1 (functional IC(50)=0.74+/-0.29 microM). Hit optimization yielded lead structure 16 with an affinity of K(i)=0.024+/-0.001 microM and greater than 1000-fold selectivity for mGluR1 versus mGluR5. Homology-based receptor modelling suggests a binding site compatible with previously reported mutation studies. Our study demonstrates the usefulness of ligand-based virtual screening for scaffold-hopping and rapid lead structure identification in early drug discovery projects.
我们报告了通过虚拟筛选和后续命中优化鉴定新型强效和选择性代谢型谷氨酸受体1（mGluR1）拮抗剂的过程。对于基于配体的虚拟筛选，分子由拓扑药效团描述符（CATS-2D）表示，并通过自组织映射（SOM）进行聚类。最有前景的化合物在mGluR1功能和结合试验中进行了测试。我们鉴定出一种强效化学类型，在mGluR1上表现出选择性拮抗活性（功能IC(50)=0.74±0.29微摩尔）。命中优化产生了先导结构16，其亲和力K(i)=0.024±0.001微摩尔，对mGluR1与mGluR5的选择性大于1000倍。基于同源性的受体建模表明存在一个与先前报道的突变研究兼容的结合位点。我们的研究证明了基于配体的虚拟筛选在早期药物发现项目中用于骨架跳跃和快速鉴定先导结构的有用性。
