Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiL<sub>X</sub>)
M.R. Bentley, O.V. Ilyichova, Geqing Wang, M.L. Williams, Gaurav Sharma, Wesam S. Alwan, Rebecca L. Whitehouse, Biswaranjan Mohanty, Peter J. Scammells, Begoña Heras, Jennifer L. Martin, Makrina Totsika, Ben Capuano, B.C. Doak, M.J. Scanlon
Abstract
A bottleneck in fragment-based lead development is the lack of systematic approaches to elaborate the initial fragment hits, which usually bind with low affinity to their target. Herein, we describe an analysis using X-ray crystallography of a diverse library of compounds prepared using microscale parallel synthesis. This approach yielded an 8-fold increase in affinity and detailed structural information for the resulting complex, providing an efficient and broadly applicable approach to early fragment development.