Wei Dengguo, Jiang Xiaolu, Zhou Lu, Chen Jing, Chen Zheng, He Chong, Yang Kun, Liu Ying, Pei Jianfeng, Lai Luhua
Beijing National Laboratory for Molecular Sciences, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
J Med Chem. 2008 Dec 25;51(24):7882-8. doi: 10.1021/jm8010096.
Multitarget drugs have been to be found effective in controlling complex diseases. However, how to design multitarget drugs presents a great challenge. We have developed a computer-assisted strategy to screen for multitarget inhibitors using a combination of molecular docking and common pharmacophore matching. This strategy was successfully applied to screen for dual-target inhibitors against both the human leukotriene A(4) hydrolase (LTA4H-h) and the human nonpancreatic secretory phospholipase A2 (hnps-PLA2). Three compounds screened from the chemical database MDL Available Chemical Directory were found to inhibit these two enzymes at the 10 microM level. Moreover, one synthetic compound matching the common pharmacophores inhibits LTA4H-h and hnps-PLA2 with IC(50) values of 35 nM and 7.3 microM, respectively. The common pharmacophore model can also be used to search small molecule databases or collections of existing inhibitors, as well as to guide combinatorial library design to search for ideal multitarget inhibitors.
多靶点药物已被证明在控制复杂疾病方面有效。然而，如何设计多靶点药物是一个巨大的挑战。我们开发了一种计算机辅助策略，通过分子对接和共同药效团匹配相结合的方法来筛选多靶点抑制剂。该策略已成功应用于筛选针对人白三烯A(4)水解酶（LTA4H-h）和人非胰腺分泌型磷脂酶A2（hnps-PLA2）的双靶点抑制剂。从化学数据库MDL可获得化学目录中筛选出的三种化合物在10 microM水平上抑制这两种酶。此外，一种符合共同药效团的合成化合物分别以35 nM和7.3 microM的IC(50)值抑制LTA4H-h和hnps-PLA2。共同药效团模型还可用于搜索小分子数据库或现有抑制剂集合，以及指导组合文库设计以寻找理想的多靶点抑制剂。
