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NMR screening applied to the fragment-based generation of inhibitors of creatine kinase exploiting a new interaction proximate to the ATP binding site.

Bretonnet AS, Jochum A, Walker O, Krimm I, Goekjian P, Marcillat O, Lancelin JM

Laboratoire de RMN et Spectrométrie de Masse Biomoléculaires, Université Claude Bernard Lyon 1, UMR CNRS 5180 Sciences Analytiques, ESCPE Lyon, France.

Using an in-house fragment NMR library, we identified a set of ligands that bind rabbit muscular creatine kinase, an enzyme involved in key ATP-dependent processes. The ligands docked to the crystal structures of creatine kinase indicated that a phenylfuroic acid could enter into a pocket adjacent to the nucleotide binding site. This fragment served as an anchor to develop in silico a series of potential inhibitors which could partly access the nucleotide binding site. The short synthesis of only four derivatives provided entirely novel hit compounds that reversibly inhibit creatine kinase at micromolar concentrations with a mixed ATP-competitive/noncompetitive mechanism in agreement with the structural model of the inhibited enzyme. These initial biologically active compounds are novel and modular and exploit a new interaction proximate to the ATP binding site.

Published 12 April 2007 in J Med Chem, 50(8): 1865-75.
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