Identifying
ligand
binding sites on proteins is a critical step
in target-based drug discovery. Current approaches to this require
resource-intensive screening of large libraries of lead-like or fragment
molecules. Here, we describe an efficient and effective experimental
approach to mapping interaction sites using a set of halogenated compounds
expressing paired hydrogen-bonding motifs, termed FragLites. The FragLites
identify productive drug-like interactions, which are identified sensitively
and unambiguously by X-ray crystallography, exploiting the anomalous
scattering of the halogen substituent. This mapping of protein interaction
surfaces provides an assessment of druggability and can identify efficient
start points for the de novo design of hit molecules incorporating
the interacting motifs. The approach is illustrated by mapping cyclin-dependent
kinase 2, which successfully identifies orthosteric and allosteric
sites. The hits were rapidly elaborated to develop efficient lead-like
molecules. Hence, the approach provides a new method of identifying
ligand sites, assessing tractability and discovering new leads.
A new method for the synthesis of 4-oxo-2-butenoic acids is described by aldol condensation with methyl ketones. Substrate dependent conditions are rationalised mechanistically with quantum mechanically derived molecular orbital energies.
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