Leveraging fragment-based drug discovery to advance 3D scaffolds into potent ligands: application to the histamine H₁ receptor.

ABSTRACT: Fragment-based drug discovery (FBDD) often relies on screening simple, 2D aromatic fragments, with the introduction of 3D character typically being reserved for later stages of hit optimization. The use of 3D screening fragments has been limited because of concerns about reduced hit rates and limited availability arising from synthetic accessibility constraints. Consequently, the chemical diversity of screening libraries has been restricted, and the potential of 3D scaffolds remains underexplored. To address these limitations, we developed novel synthetic methodologies for constructing 3D scaffolds and integrated them into FBDD workflows, which we consider an optimal strategy to advance these chemistries into hit optimization programs. Here, we report the screening of a focused 3D fragment

SUBMITTER: Dekker T 

PROVIDER: S-EPMC12895670 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature