Improving Binding Specificity of Pharmacological Chaperones That Target Mutant Superoxide Dismutase-1 Linked to Familial Amyotrophic Lateral Sclerosis Using Computational Methods


We recently described a set of drug-like molecules obtained from an in silico screen that stabilize mutant superoxide dismutase-1 (SOD-1) linked to familial amyotrophic lateral sclerosis (ALS) against unfolding and aggregation but exhibited poor binding specificity toward SOD-1 in presence of blood plasma. A reasonable but not a conclusive model for the binding of these molecules was proposed on the basis of restricted docking calculations and site-directed mutagenesis of key residues at the dimer interface. A set of hydrogen bonding constraints obtained from these experiments were used to guide docking calculations with compound library around the dimer interface. A series of chemically unrelated hits were predicted, which were experimentally tested for their ability to block aggregation. At least six of the new molecules exhibited high specificity of binding toward SOD-1 in the presence of blood plasma. These molecules represent a new class of molecules for further development into clinical candidates.




Copyright 2010 Journal of Medicinal Chemistry. This is a post-print version of a published paper that is available at: Recommended citation: Nowak, Richard J., Gregory D. Cuny, Sungwoon Choi, Peter T. Lansbury, and Soumya S. Ray. "Improving binding specificity of pharmacological chaperones that target mutant superoxide dismutase-1 linked to familial amyotrophic lateral sclerosis using computational methods." Journal of medicinal chemistry 53, no. 7 (2010): 2709-2718. doi: 10.1021/jm901062p. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.