title: Structural discovery of small molecule binding sites in Cu-Zn human superoxide dismutase familial amyotrophic lateral sclerosis mutants provides insights for lead optimization.
abstract: Dominant inheritance of point mutations in CuZn superoxide dismutase (SOD1) is the best characterized subset of familial amyotrophic lateral sclerosis (FALS) and accounts for some 20% of the known familial cases. We report the discovery and visualization via cocrystallography of two ligand-binding pockets in human SOD1 and its pathogenic mutants that have opened up the real possibility of undertaking lead compound discovery using a fragment-based approach for therapeutic purposes for SOD1 associated motor neuron disease.
authors.affiliation: Molecular Biophysics Group, School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, UK.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Antonyuk
authors.forename: Richard W
authors.initials: RW
authors.lastname: Strange
authors.forename: S Samar
authors.initials: SS
authors.lastname: Hasnain
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D008956:Models, Chemical; D009154:Mutation / Q000235:genetics*; D054852:Small Molecule Libraries; D013482:Superoxide Dismutase / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D054852:Small Molecule Libraries; D013482:Superoxide Dismutase