title: NMR screening applied to the fragment-based generation of inhibitors of creatine kinase exploiting a new interaction proximate to the ATP binding site.
abstract: 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.
authors: Laboratoire de RMN et Spectrométrie de Masse Biomoléculaires, Université Claude Bernard Lyon 1, UMR CNRS 5180 Sciences Analytiques, ESCPE Lyon, France.
authors: Anne-Sophie
authors: AS
authors: Bretonnet
authors: Anne
authors: A
authors: Jochum
authors: Olivier
authors: O
authors: Walker
authors: Isabelle
authors: I
authors: Krimm
authors: Peter
authors: P
authors: Goekjian
authors: Olivier
authors: O
authors: Marcillat
authors: Jean-Marc
authors: JM
authors: Lancelin
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry*; D000818:Animals; D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D003402:Creatine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry; D006868:Hydrolysis; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D011817:Rabbits
chemical_list: D001555:Benzene Derivatives; D005663:Furans; D008024:Ligands; D000255:Adenosine Triphosphate; D003402:Creatine Kinase; C060089:2-furoic acid