title: Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation.
abstract: Familial amyotrophic lateral sclerosis (FALS) is a fatal motor neuron disease that is caused by mutations in the gene encoding superoxide dismutase-type 1 (SOD1). The affected regions of the FALS brain are characterized by aggregated SOD1, and the mutations that destabilize SOD1 appear to promote its aggregation in vitro. Because dissociation of the native SOD1 dimer is required for its in vitro aggregation, we initiated an in silico screening program to find drug-like molecules that would stabilize the SOD1 dimer. A potential binding site for such molecules at the SOD1 dimer interface was identified, and its importance was validated by mutagenesis. About 1.5 million molecules from commercial databases were docked at the dimer interface. Of the 100 molecules with the highest predicted binding affinity, 15 significantly inhibited in vitro aggregation and denaturation of A4V, a FALS-linked variant of SOD1. In the presence of several of these molecules, A4V and other FALS-linked SOD1 mutants such as G93A and G85R behaved similarly to wild-type SOD1, suggesting that these compounds could be leads toward effective therapeutics against FALS.
authors.affiliation: Harvard Center for Neurodegeneration and Repair and Department of Neurology, Harvard Medical School, Boston, MA 02115, USA. sray@rics.bwh.harvard.edu
authors.forename: Soumya S
authors.initials: SS
authors.lastname: Ray
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Nowak
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Peter T
authors.initials: PT
authors.lastname: Lansbury
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D001665:Binding Sites; D019281:Dimerization; D006801:Humans; D009154:Mutation; D011489:Protein Denaturation; D017510:Protein Folding; D013482:Superoxide Dismutase / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D000072105:Superoxide Dismutase-1
chemical_list: C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
references.citation: Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12571-6
references.pmid: 11050163
references.citation: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references.pmid: 11259830
references.citation: Science. 2001 Sep 28;293(5539):2459-62
references.pmid: 11577236
references.citation: J Biol Chem. 2002 May 3;277(18):15923-31
references.pmid: 11854284
references.citation: Structure. 2002 Jun;10(6):851-63
references.pmid: 12057199
references.citation: Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):16607-12
references.pmid: 12482932
references.citation: Biochemistry. 1992 May 26;31(20):4901-7
references.pmid: 1591250
references.citation: Cell. 1995 Mar 10;80(5):687-92
references.pmid: 7889564
references.citation: Curr Opin Neurobiol. 1995 Dec;5(6):841-6
references.pmid: 8805422
references.citation: Ciba Found Symp. 1996;199:228-38; discussion 239-42
references.pmid: 8915613
references.citation: Neuropathol Appl Neurobiol. 1996 Oct;22(5):373-87
references.pmid: 8930947
references.citation: Proc Natl Acad Sci U S A. 1996 Dec 24;93(26):15051-6
references.pmid: 8986762
references.citation: Adv Protein Chem. 1997;50:161-81
references.pmid: 9338081
references.citation: Bioorg Med Chem. 1998 Aug;6(8):1389-401
references.pmid: 9784876
references.citation: Nat Med. 1998 Nov;4(11):1318-20
references.pmid: 9809558
references.citation: Bioorg Med Chem Lett. 1999 Jan 4;9(1):1-6
references.pmid: 9990446
references.citation: Acta Crystallogr D Biol Crystallogr. 1999 Apr;55(Pt 4):941-4
references.pmid: 10089342
references.citation: Bioorg Med Chem. 1999 Jul;7(7):1339-47
references.pmid: 10465408
references.citation: J Biol Chem. 2004 Nov 12;279(46):47998-8003
references.pmid: 15326189
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 9;101(45):15893-8
references.pmid: 15522970
references.citation: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5796-801
references.pmid: 10823938
references.citation: Biochim Biophys Acta. 2000 May 23;1478(2):325-32
references.pmid: 10825544
references.citation: J Biol Chem. 2004 Dec 24;279(52):54558-66
references.pmid: 15485869
references.citation: J Biol Chem. 2003 Feb 21;278(8):5984-92
references.pmid: 12458194
references.citation: Biochem Biophys Res Commun. 2003 Dec 26;312(4):873-6
references.pmid: 14651952
references.citation: J Med Chem. 2004 Jan 15;47(2):355-74
references.pmid: 14711308
references.citation: J Med Chem. 2004 Jan 29;47(3):558-65
references.pmid: 14736237
references.citation: J Med Chem. 2004 Mar 25;47(7):1750-9
references.pmid: 15027866
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5976-81
references.pmid: 15056757
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5701-2
references.pmid: 15079068
references.citation: Biochemistry. 2004 May 4;43(17):4899-905
references.pmid: 15109247
references.citation: EMBO J. 2004 Jul 21;23(14):2872-81
references.pmid: 15215895
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15094-9
references.pmid: 15475574
references.citation: J Biol Chem. 1969 Nov 25;244(22):6049-55
references.pmid: 5389100
references.citation: Proc Natl Acad Sci U S A. 1989 Nov;86(21):8237-41
references.pmid: 2682639