Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Benzopyran-based Inhibitors

• Inhibition of the insulin-regulated aminopeptidase (IRAP) improves memory and cognition in animal models. The enzyme has been recently crystallized and several series of inhibitors reported. We herein focused on one series of benzopyran-based inhibitors of IRAP, known as HFI series, and developed a robust computational model to explain the SAR and potentially guide the optimization of this scaffold. Our binding model positions the benzopyran ring in the catalytic binding site, coordinating the Zn+2 ion through the oxygen in position 3 of the, in contrast to previous hypothesis. The whole series of HFI compounds was systematically simulated using molecular dynamics in this binding orientation and binding affinity estimated with the linear interaction energy (LIE) method. The agreement with experimental affinities supports the binding mode proposed, which was further challenged by rigorous free energy perturbation calculations. Here, we found excellent correlation between experimental and calculated binding affinity differences, both between selected compound pairs and also for recently reported experimental data concerning the site directed mutagenesis of residue Phe544. The computationally derived structure-activity relationship of the HFI series and the demonstrated involvement of Phe544 in the binding of this scaffold provide valuable information for further lead optimization of novel IRAP inhibitors.

Ämnesord

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

Nyckelord

Biokemi

Biochemistry

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)