Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides

The insulin-regulated
aminopeptidase (IRAP) is a membrane-bound
zinc metallopeptidase with many important regulatory functions. It
has been demonstrated that inhibition of IRAP by angiotensin IV (Ang
IV) and other peptides, as well as more druglike inhibitors, improves
cognition in several rodent models. We recently reported a series
of aryl sulfonamides as small-molecule IRAP inhibitors and a promising
scaffold for pharmacological intervention. We have now expanded with
a number of derivatives, report their stability in liver microsomes,
and characterize the activity of the whole series in a new assay performed
on recombinant human IRAP. Several compounds, such as the new fluorinated
derivative 29, present submicromolar affinity and high
metabolic stability. Starting from the two binding modes previously
proposed for the sulfonamide scaffold, we systematically performed
molecular dynamics simulations and binding affinity estimation with
the linear interaction energy method for the full compound series.
The significant agreement with experimental affinities suggests one
of the binding modes, which was further confirmed by the excellent
correlation for binding affinity differences between the selected
pair of compounds obtained by rigorous free energy perturbation calculations.
The new experimental data and the computationally derived structure–activity
relationship of the sulfonamide series provide valuable information
for further lead optimization of novel IRAP inhibitors.