Conformational Changes in Insulin Regulated Aminopeptidase

Abstract: Global disease burden due to age related cognitive decline and dementias, especially Alzheimer’s disease, are a growing public health problem. Current treatments fail to completely prevent or cure dementia. A target of interest is the Insulin Regulated Aminopeptidase (IRAP) enzyme, inhibitors of IRAP have shown promise in preventing and reversing neurological degeneration associated with dementia. Structural information about IRAP when bound to an inhibitor is lacking, however, and future ligand design depends on knowledge of the mechanism of inhibition. We used long term MD simulations of IRAP bound to various ligands to investigate the conformational changes undergone by IRAP. PCA analysis was also used to investigate larger changes in the enzyme. A highly stable pose for a known spiro-oxindole inhibitor was found with key interactions between the ligand and SER546 and TYR 954, providing useful data for the design of future inhibitors of the IRAP enzyme.