Discovery of α7-Nicotinic Receptor Ligands by Virtual Screening of the Chemical Universe Database GDB-13

The chemical universe database GDB-13 enumerates 977 million organic molecules up to 13 atoms of C, N, O, Cl, and S that are virtually possible following simple rules for chemical stability and synthetic feasibility. Analogs of nicotine were identified in GDB-13 using the city-block distance in MQN-space (CBDMQN) as a similarity measure, combined with a restriction eliminating problematic structural elements. The search was carried out with a Web browser available at www.gdb.unibe.ch. This virtual screening procedure selected 31 504 analogs of nicotine from GDB-13, from which 48 were known nicotinic ligands reported in Chembl. An additional 60 virtual screening hits were purchased and tested for modulation of the acetylcholine signal at the human α7 nAChR expressed in Xenopus oocytes, which led to the identification of three previously unknown inhibitors. These experiments demonstrate for the first time the use of GDB-13 for ligand discovery.

化学宇宙数据库GDB-13收录了9.77亿个有机分子，这些分子仅包含碳、氮、氧、氯与硫五种元素，原子总数不超过13个，且遵循化学稳定性与合成可行性的简单规则，理论上均具备存在可能性。研究人员以MQN空间（MQN-space）内的城市街区距离（CBDMQN）作为相似性度量标准，并结合剔除存在问题结构单元的筛选限制条件，从GDB-13中鉴定尼古丁类似物。本次筛选可通过访问www.gdb.unibe.ch的网页端工具完成操作。本次虚拟筛选流程从GDB-13中筛选得到31504个尼古丁类似物，其中48个为已报道的烟碱类配体，相关记录收录于ChEMBL数据库（Chembl）。研究人员额外采购了60个虚拟筛选命中化合物，针对表达于非洲爪蟾卵母细胞（Xenopus oocytes）的人源α7烟碱型乙酰胆碱受体（α7 nAChR）的乙酰胆碱信号调控活性开展测试，最终发现3种此前未被报道的抑制剂。本实验首次证实了GDB-13在配体发现领域的应用价值。