uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Aryl Sulfonamides
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry.
Monash Univ, Biomed Discovery Inst, Dept Physiol, Clayton, Vic 3800, Australia.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Preparative Medicinal Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0001-6258-0635
Show others and affiliations
2018 (English)In: ACS OMEGA, ISSN 2470-1343, Vol. 3, no 4, p. 4509-4521Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC , 2018. Vol. 3, no 4, p. 4509-4521
National Category
Biochemistry and Molecular Biology Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-358572DOI: 10.1021/acsomega.8b00595ISI: 000434352800025PubMedID: 30023895OAI: oai:DiVA.org:uu-358572DiVA, id: diva2:1248812
Funder
Swedish Research CouncilAvailable from: 2018-09-17 Created: 2018-09-17 Last updated: 2018-09-17Bibliographically approved

Open Access in DiVA

fulltext(6513 kB)71 downloads
File information
File name FULLTEXT01.pdfFile size 6513 kBChecksum SHA-512
c0cc9ad705b5c8818312c33b34bda9eb6865349f7beb7034f721e25f3d4826a79b0bd14b7efae6ebe3a2628af5920b517f94ed3afdb4731ce4828e610f506e6c
Type fulltextMimetype application/pdf

Other links

Publisher's full textPubMed

Authority records BETA

Reddy Vanga, SudarsanaSävmarker, JonasLarhed, MatsHallberg, MathiasÅqvist, JohanHallberg, AndersGutiérrez-de-Terán, Hugo

Search in DiVA

By author/editor
Reddy Vanga, SudarsanaSävmarker, JonasLarhed, MatsHallberg, MathiasÅqvist, JohanHallberg, AndersGutiérrez-de-Terán, Hugo
By organisation
Computational Biology and BioinformaticsPreparative Medicinal ChemistryScience for Life Laboratory, SciLifeLabDepartment of Pharmaceutical Biosciences
Biochemistry and Molecular BiologyMedicinal Chemistry

Search outside of DiVA

GoogleGoogle Scholar
Total: 71 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 135 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf