Meier Kris, Bühlmann Sven, Arús-Pous Josep, Reymond Jean-Louis
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland.
Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012 Bern, Switzerland;, Email:
Chimia (Aarau). 2020 Apr 29;74(4):241-246. doi: 10.2533/chimia.2020.241.
Drug discovery is in constant need of new molecules to develop drugs addressing unmet medical needs. To assess the chemical space available for drug design, our group investigates the generated databases (GDBs) listing all possible organic molecules up to a defined size, the largest of which is GDB-17 featuring 166.4 billion molecules up to 17 non-hydrogen atoms. While known drugs and bioactive compounds are mostly aromatic and planar, the GDBs contain a plethora of non-aromatic 3D-shaped molecules, which are very useful for drug discovery since they generally have more desirable absorption, distribution, metabolism, excretion and toxicity (ADMET) properties. Here we review GDB enumeration methods and the selection and synthesis of GDB molecules as modulators of ion channels. We summarize the constitution of GDB subsets focusing on fragments (FDB17), medicinal chemistry (GDBMedChem) and ChEMBL-like molecules (GDBChEMBL), and the ring system database GDB4c as a rich source of novel 3D-shaped chiral molecules containing quaternary centers, such as the recently reported trinorbornane.
药物研发一直需要新的分子来开发满足未满足医疗需求的药物。为了评估可用于药物设计的化学空间，我们团队研究了生成数据库（GDB），这些数据库列出了所有直至特定大小的可能有机分子，其中最大的是GDB-17，包含多达1664亿个含17个非氢原子的分子。虽然已知药物和生物活性化合物大多是芳香族和平平面状的，但GDB包含大量非芳香族的三维形状分子，这些分子对药物研发非常有用，因为它们通常具有更理想的吸收、分布、代谢、排泄和毒性（ADMET）特性。在此，我们综述了GDB枚举方法以及作为离子通道调节剂的GDB分子的选择与合成。我们总结了GDB子集的构成，重点关注片段（FDB17）、药物化学（GDBMedChem）和类似ChEMBL的分子（GDBChEMBL），以及环系数据库GDB4c，它是含有季中心的新型三维形状手性分子的丰富来源，例如最近报道的三环壬烷。
