Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Magyar tudósok krt. 2, H-1117 Budapest, Hungary.
Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, SI-1000 Ljubljana, Slovenia.
Molecules. 2019 Jul 16;24(14):2590. doi: 10.3390/molecules24142590.
Large-scale virtual screening of boronic acid derivatives was performed to identify nonpeptidic covalent inhibitors of the β5i subunit of the immunoproteasome. A hierarchical virtual screening cascade including noncovalent and covalent docking steps was applied to a virtual library of over 104,000 compounds. Then, 32 virtual hits were selected, out of which five were experimentally confirmed. Biophysical and biochemical tests showed micromolar binding affinity and time-dependent inhibitory potency for two compounds. These results validate the computational protocol that allows the screening of large compound collections. One of the lead-like boronic acid derivatives identified as a covalent immunoproteasome inhibitor is a suitable starting point for chemical optimization.
采用大规模虚拟筛选硼酸衍生物的方法，以鉴定免疫蛋白酶体β5i 亚基的非肽共价抑制剂。采用包含非共价和共价对接步骤的分层虚拟筛选级联，对超过 104000 种化合物的虚拟库进行了筛选。然后，从 32 个虚拟命中物中选择了 5 个进行实验验证。生物物理和生化测试表明，两种化合物具有微摩尔结合亲和力和时间依赖性抑制效力。这些结果验证了可以筛选大型化合物库的计算方案。鉴定出的一种类似先导的硼酸衍生物作为共价免疫蛋白酶体抑制剂，是进行化学优化的合适起点。
