Design and Synthesis of 56 Shape-Diverse 3D Fragments.

摘要: 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 design and synthesis of 56 3D disubstituted pyrrolidine piperidine fragments that occupy under-represented areas space (as demonstrated by principal moments inertia (PMI) analysis). A key, unique, underpinning feature this collection assessment shape conformational diversity (by considering conformations up to 1.5 kcal mol-1 above energy global minimum conformer) carried out prior also used select targets synthesis. The 3D were designed contain suitable synthetic handles future elaboration. Finally, comparing our six commercial libraries, it clear has high three-dimensionality diversity.