title: Probing the ATP-Binding Pocket of Protein Kinase DYRK1A with Benzothiazole Fragment Molecules.
abstract: DYRK1A has emerged as a potential target for therapies of Alzheimer's disease using small molecules. On the basis of the observation of selective DYRK1A inhibition by firefly d-luciferin, we have explored static and dynamic structural properties of fragment sized variants of the benzothiazole scaffold with respect to DYRK1A using X-ray crystallography and NMR techniques. The compounds have excellent ligand efficiencies and show a remarkable diversity of binding modes in dynamic equilibrium. Binding geometries are determined in part by interactions often considered "weak", including "orthogonal multipolar" types represented by, for example, F-CO, sulfur-aromatic, and halogen-aromatic interactions, together with hydrogen bonds that are modulated by variation of electron withdrawing groups. These studies show how the benzothiazole scaffold is highly promising for the development of therapeutic DYRK1A inhibitors. In addition, the subtleties of the binding interactions, including dynamics, show how full structural studies are required to fully interpret the essential physical determinants of binding.
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.|Pharmasum Therapeutics AS , Smørblomstvn. 36, N-9102 Kvaløysletta, Norway.
authors.forename: Ulli
authors.initials: U
authors.lastname: Rothweiler
authors.affiliation: Pharmasum Therapeutics AS , Smørblomstvn. 36, N-9102 Kvaløysletta, Norway.|Department of Chemistry, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
authors.forename: Wenche
authors.initials: W
authors.lastname: Stensen
authors.affiliation: The Centre of Theoretical and Computational Chemistry, Department of Chemistry, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
authors.forename: Bjørn Olav
authors.initials: BO
authors.lastname: Brandsdal
authors.affiliation: Department of Chemistry, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
authors.forename: Johan
authors.initials: J
authors.lastname: Isaksson
authors.affiliation: Pharmasum Therapeutics AS , Smørblomstvn. 36, N-9102 Kvaløysletta, Norway.|Department of Chemistry, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
authors.forename: Frederick Alan
authors.initials: FA
authors.lastname: Leeson
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
authors.forename: Richard Alan
authors.initials: RA
authors.lastname: Engh
authors.affiliation: Pharmasum Therapeutics AS , Smørblomstvn. 36, N-9102 Kvaløysletta, Norway.|Department of Chemistry, UiT The Arctic University of Norway , N-9037 Tromsø, Norway.
authors.forename: John S Mjøen
authors.initials: JS
authors.lastname: Svendsen
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000097603:Dyrk Kinases
chemical_list: D052160:Benzothiazoles; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D000097603:Dyrk Kinases; C005465:benzothiazole