Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Freiestrasse 3, 3012 Bern, Switzerland.
J Chem Inf Model. 2023 Oct 23;63(20):6239-6248. doi: 10.1021/acs.jcim.3c01096. Epub 2023 Sep 18.
Identifying innovative fragments for drug design can help medicinal chemistry address new targets and overcome the limitations of the classical molecular series. By deconstructing molecules into ring fragments (RFs, consisting of ring atoms plus ring-adjacent atoms) and acyclic fragments (AFs, consisting of only acyclic atoms), we find that public databases of molecules (i.e., ZINC and PubChem) and natural products (i.e., COCONUT) contain mostly RFs and AFs of up to 13 atoms. We also find that many RFs and AFs are enriched in bioactive vs inactive compounds from ChEMBL. We then analyze the generated database GDB-13s, which enumerates 99 million possible molecules of up to 13 atoms, for RFs and AFs resembling ChEMBL bioactive RFs and AFs. This analysis reveals a large number of novel RFs and AFs that are structurally simple, have favorable synthetic accessibility scores, and represent opportunities for synthetic chemistry to contribute to drug innovation in the context of fragment-based drug discovery.
鉴定药物设计的创新片段有助于药物化学针对新靶点，并克服经典分子系列的局限性。通过将分子分解为环片段（RFs，由环原子加环相邻原子组成）和无环片段（AFs，仅由无环原子组成），我们发现分子的公共数据库（即 ZINC 和 PubChem）和天然产物（即 COCONUT）主要包含最多 13 个原子的 RFs 和 AFs。我们还发现，许多 RFs 和 AFs 在 ChEMBL 的生物活性与非活性化合物中更为丰富。然后，我们分析了生成的数据库 GDB-13s，它枚举了 9900 万个可能的最多 13 个原子的分子，用于与 ChEMBL 生物活性 RFs 和 AFs 相似的 RFs 和 AFs。该分析揭示了大量结构简单、具有良好合成可及性评分的新型 RFs 和 AFs，为合成化学在基于片段的药物发现背景下为药物创新做出贡献提供了机会。
