Hefke Lena, Hiesinger Kerstin, Zhu W Felix, Kramer Jan S, Proschak Ewgenij
Institute of Pharmaceutical Chemistry, Goethe-University, Max-von-Laue Strasse 9, D-60438 Frankfurt, Germany.
ACS Med Chem Lett. 2020 Apr 8;11(6):1244-1249. doi: 10.1021/acsmedchemlett.0c00102. eCollection 2020 Jun 11.
Multitarget ligands are interesting candidates for drug discovery and development due to improved safety and efficacy. However, rational design and optimization of multitarget ligands is tedious because affinity optimization for two or more targets has to be performed simultaneously. In this study, we demonstrate that, given a molecular fragment, which binds to two targets of interest, computer-aided fragment growing can be applied to optimize compound potency, relying on either ligand- or structure-derived information. This methodology is applied to the design of dual inhibitors of soluble epoxide hydrolase and leukotriene A4 hydrolase.
由于安全性和有效性的提高，多靶点配体是药物发现和开发中令人感兴趣的候选物。然而，多靶点配体的合理设计和优化是繁琐的，因为必须同时对两个或更多靶点进行亲和力优化。在本研究中，我们证明，给定一个与两个感兴趣的靶点结合的分子片段，可以应用计算机辅助片段生长来优化化合物的效力，这依赖于配体或结构衍生的信息。该方法应用于可溶性环氧化物水解酶和白三烯A4水解酶双重抑制剂的设计。
