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

TL;DR

This paper shows how using 3D chemical structures in drug discovery can lead to finding potent compounds for the histamine H1 receptor.

Contribution

The study introduces new methods for incorporating 3D scaffolds into fragment-based drug discovery workflows.

Findings

A cyclobutane-containing hit was identified for the histamine H1 receptor.

A high-affinity antagonist (VUF26691) was developed with a pKi of 8.8.

FBDD successfully translated 3D chemistries into biologically active compounds.

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, pKi = 8.8). Overall, we demonstrate that FBDD is an efficient method to achieve the incorporation of novel (3D) chemistries into biologically active compounds.

Fragment-based drug discovery enables translation of novel (3D) chemistries into biologically relevant hit matter, as demonstrated by the identification and optimization of a cyclobutane-based 3D fragment into a potent histamine H1 receptor ligand.

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