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

ACS Omega
Sudarsana Reddy VangaHugo Gutiérrez-de-Terán

Abstract

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 ...Continue Reading

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Citations

Oct 20, 2020·Frontiers in Pharmacology·Dimitris GeorgiadisAntonia Papasava
Dec 17, 2019·Journal of Medicinal Chemistry·Zachary MabenLawrence J Stern
Nov 13, 2020·Frontiers in Pharmacology·Mathias Hallberg, Mats Larhed
Jan 23, 2021·RSC Medicinal Chemistry·Nicholas BarlowPhilip E Thompson
Feb 8, 2020·Journal of Medicinal Chemistry·Lucienne Juillerat-Jeanneret
Apr 20, 2021·Frontiers in Molecular Biosciences·Sudarsana Reddy VangaHugo Gutiérrez-de-Terán
Jan 19, 2022·Drug Development Research·Cauê Benito Scarim, Fernando Rogério Pavan

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Software Mentioned

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