Leveraging fragment-based drug discovery to advance 3D scaffolds into potent ligands: application to the histamine H ₁ 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 library and the identification of a cyclobutane-containing hit for the histamine H₁ receptor. A subsequent hit exploration yielded high-affinity antagonist 17a (VUF26691, pK _i = 8.8). Overall, we demonstrate that FBDD is an efficient method to achieve the incorporation of novel (3D) chemistries into biologically active compounds.