Accessing a Medicinal-Chemistry-Relevant Chemical Space with sp2–sp3 Hybrid Heterocyclic Fragments

Synthesis Pub Date : 2024-09-09 DOI:10.1055/s-0040-1720137
Raquel Mato, Colin Bournez, Quentin Lefebvre
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Abstract

Target-first drug discovery relies heavily on protein structure information, which severely limits its application. In recent years, fragment-based drug Design (FBDD) has been identified as an alternative solution, where screening of smaller molecules for lower affinity allowed the use of focused libraries with a higher hit rate. It is shown that coupling an sp2-rich heteroaromatic group with a monofunctional sp3-rich core gives fragments (186 examples) with advantageous physical-chemical properties, covering a chemical space often neglected in traditional libraries.

Abstract Image

利用 sp2-sp3 杂环片段进入药物化学相关的化学空间
靶向药物发现主要依赖蛋白质结构信息,这严重限制了其应用。近年来,基于片段的药物设计(FBDD)被认为是另一种解决方案,通过筛选亲和力较低的小分子,可以使用命中率较高的集中库。研究表明,将一个富含 sp2 的杂芳香基团与一个富含 sp3 的单官能团核心耦合,可以得到具有优势物理化学性质的片段(186 个实例),这些片段覆盖了传统库中经常被忽视的化学空间。
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