Design and Synthesis of 56 Shape-Diverse 3D Fragments

Abstract

Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol^-1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.

Keywords: 3D fragments; conformational diversity; fragment-based drug discovery; medicinal chemistry; synthesis design.

Figure 1

PMI analysis of potential fragments. A: Conformers of pyrrolidine scaffold 1 (top) and exemplar fragments (bottom). B: Conformers of piperidine scaffold 2 (top) and exemplar fragments (bottom). Compounds with conformations within the grey areas were selected for synthesis. C: Conformers of 33 selected fragments (top) and global minimum energy and selected higher energy 3D conformers of 1 l and 2 j. Red dots indicate global minimum energy conformers and blue dots indicate higher energy conformers.

Scheme 1

Synthesis of selected 3D fragments.

Figure 2

Additional structurally diverse 3D fragments.

Figure 3

A: PMI plot of the final fragment collection. Red dots indicate global minimum energy conformers and blue dots indicate higher energy conformers. B: Cumulative PMI analysis of the fragment collection (light blue) along with six commercially available libraries.