Zhong Shijun, Chen Xi, Zhu Xiao, Dziegielewska Barbara, Bachman Kurtis E, Ellenberger Tom, Ballin Jeff D, Wilson Gerald M, Tomkinson Alan E, MacKerell Alexander D
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
J Med Chem. 2008 Aug 14;51(15):4553-62. doi: 10.1021/jm8001668. Epub 2008 Jul 17.
Linking together of DNA strands by DNA ligases is essential for DNA replication and repair. Since many therapies used to treat cancer act by causing DNA damage, there is growing interest in the development of DNA repair inhibitors. Accordingly, virtual database screening and experimental evaluation were applied to identify inhibitors of human DNA ligase I (hLigI). When a DNA binding site within the DNA binding domain (DBD) of hLigI was targeted, more than 1 million compounds were screened from which 192 were chosen for experimental evaluation. In DNA joining assays, 10 compounds specifically inhibited hLigI, 5 of which also inhibited the proliferation of cultured human cell lines. Analysis of the 10 active compounds revealed the utility of including multiple protein conformations and chemical clustering in the virtual screening procedure. The identified ligase inhibitors are structurally diverse and have druglike physical and molecular characteristics making them ideal for further drug development studies.
DNA连接酶将DNA链连接在一起对于DNA复制和修复至关重要。由于许多用于治疗癌症的疗法是通过造成DNA损伤来发挥作用的，因此人们对开发DNA修复抑制剂的兴趣与日俱增。相应地，运用虚拟数据库筛选和实验评估来鉴定人DNA连接酶I（hLigI）的抑制剂。当靶向hLigI的DNA结合结构域（DBD）内的一个DNA结合位点时，从超过100万种化合物中进行了筛选，从中挑选出192种用于实验评估。在DNA连接测定中，有10种化合物特异性抑制hLigI，其中5种还抑制培养的人细胞系的增殖。对这10种活性化合物的分析揭示了在虚拟筛选过程中纳入多种蛋白质构象和化学聚类的效用。所鉴定的连接酶抑制剂在结构上具有多样性，并且具有类药物的物理和分子特性，使其非常适合进一步的药物开发研究。
