Structural discovery of small molecule binding sites in Cu-Zn human superoxide dismutase familial amyotrophic lateral sclerosis mutants provides insights for lead optimization

Svetlana Antonyuk; Richard W Strange; S Samar Hasnain

doi:10.1021/jm9017948

Structural discovery of small molecule binding sites in Cu-Zn human superoxide dismutase familial amyotrophic lateral sclerosis mutants provides insights for lead optimization

J Med Chem. 2010 Feb 11;53(3):1402-6. doi: 10.1021/jm9017948.

Authors

Svetlana Antonyuk¹, Richard W Strange, S Samar Hasnain

Affiliation

¹ Molecular Biophysics Group, School of Biological Sciences, University of Liverpool, Liverpool L69 7ZB, UK.

PMID: 20067275
DOI: 10.1021/jm9017948

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis / drug therapy
Amyotrophic Lateral Sclerosis / enzymology*
Amyotrophic Lateral Sclerosis / genetics
Binding Sites
Crystallography, X-Ray
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Hydrogen Bonding
Models, Chemical
Mutation / genetics*
Small Molecule Libraries
Superoxide Dismutase / chemistry*

Substances

Enzyme Inhibitors
Small Molecule Libraries
Superoxide Dismutase