Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiL(x))
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Ilyichova, Olga V
Wang, Geqing
Williams, Martin L
Sharma, Gaurav
Alwan, Wesam S
Whitehouse, Rebecca L
Mohanty, Biswaranjan
Scammells, Peter J
Heras, Begona
Martin, Jennifer L
Totsika, Makrina
Capuano, Ben
Doak, Bradley C
Scanlon, Martin J
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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.
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Journal of Medicinal Chemistry
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63
Issue
13
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APP1099151
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Medicinal and biomolecular chemistry
Organic chemistry
Pharmacology and pharmaceutical sciences
Science & Technology
Life Sciences & Biomedicine
Chemistry, Medicinal
Pharmacology & Pharmacy
SPACE
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Bentley, MR; Ilyichova, OV; Wang, G; Williams, ML; Sharma, G; Alwan, WS; Whitehouse, RL; Mohanty, B; Scammells, PJ; Heras, B; Martin, JL; Totsika, M; Capuano, B; Doak, BC; Scanlon, MJ, Rapid Elaboration of Fragments into Leads by X-ray Crystallographic Screening of Parallel Chemical Libraries (REFiL(x)), Journal of Medicinal Chemistry, 2020, 63 (13), pp. 6863-6875