Structural Elucidation of a Small Molecule Inhibitor of Protein Disulfide Isomerase.
Compound libraries provide a starting point for multiple biological investigations, but the structural integrity of compounds is rarely assessed experimentally until a late stage in the research process. Here, we describe the discovery of a neuroprotective small molecule that was originally incorrectly annotated with a chemical structure. We elucidated the correct structure of the active compound using analytical chemistry, revealing it to be the natural product securinine. We show that securinine is protective in a cell model of Huntington disease and identify the binding site of securinine to its target, protein disulfide isomerase using NMR chemical shift perturbation studies. We show that securinine displays favorable pharmaceutical properties, making it a promising compound forin vivostudies in neurodegenerative disease models. In addition to finding this unexpected activity of securinine, this study provides a systematic roadmap to those who encounter compounds with incorrect structural annotation in the course of screening campaigns.
Department of Biological Sciences, Department of Chemistry, and Howard Hughes Medical Institute, Columbia University , 1208 Northwest Corner Building, MC4846, 550 West 120th Street, New York, New York 10027, United States.
Anna
A
Kaplan
Department of Biological Sciences, Department of Chemistry, and Howard Hughes Medical Institute, Columbia University , 1208 Northwest Corner Building, MC4846, 550 West 120th Street, New York, New York 10027, United States.
Brent R
BR
Stockwell
PDI; Structure elucidation; high-throughput screen; natural product; neuroprotection