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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
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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: 2019-10-16Bibliographically approved
In thesis
1. Probing Ligand Binding Mechanisms in Insulin-Regulated Aminopeptidases: Computational analysis and free energy calculations of binding modes
Open this publication in new window or tab >>Probing Ligand Binding Mechanisms in Insulin-Regulated Aminopeptidases: Computational analysis and free energy calculations of binding modes
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In recent years insulin-regulated aminopeptidase (IRAP) has emerged as a new therapeutic target for the treatment of Alzheimer’s disease and other memory-related disorders. So far, many potent and specific IRAP inhibitors had been disclosed, including peptides, peptidomimetics, and low-molecular-weight sulfonamides. In this thesis, various computational approaches such as docking, molecular dynamics (MD), linear interaction energy (LIE), and free energy perturbations (FEP) are used to understand the molecular basis for the binding of these inhibitors to the IRAP.

By applying MD and LIE, the binding mode of Ang IV and the critical role of its N-terminal tripeptide in the binding to IRAP were described. The stark difference in the binding properties of two stereoisomers of a peptidomimetic inhibitor, HA08 and HA09, was determined using MD simulations and LIE binding affinity estimations. With the help of the FEP method, we discriminate the most probable, between two alternative binding poses for the sulfonamide family of compounds. The binding modes of the HFI family of compounds (competitive inhibitors), and spiro-oxindole compounds (allosteric, uncompetitive inhibitors) were also proposed utilizing a combination of related computational approaches. In this thesis, the specificity of the diverse class of inhibitors and substrates (oxytocin and vasopressin) for IRAP compared to other M1 aminopetidase family members was disclosed as a result of the unique Gly-Ala-Met-Glu-Asn (GAMEN) loop orientation. The different studies performed along this thesis resulted in several proposed binding modes, which were evaluated by different free energy calculation approaches, namely LIE and FEP methods. In all cases, the calculated free energies are in excellent agreement with the experimental data, which strongly supports the final binding models here proposed.

These results of this thesis will be useful in future lead generation and optimization process and hopefully in the development of better cognitive enhancers for the treatment of dementia and other related diseases such as Alzheimer’s disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. p. 64
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1870
Keywords
Docking, Molecular Dynamics, Binding free energy, Linear Interaction Energy, Free Energy Perturbation, Insulin-Regulated Aminopeptidase, Angiotensin IV, Oxytocin, Vasopressin, HA08, Aryl sulfonamides, HFI compounds.
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-395295 (URN)978-91-513-0784-8 (ISBN)
Public defence
2019-12-06, B42, Biomedicinskt centrum (BMC), Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-11-13 Created: 2019-10-16 Last updated: 2019-11-13

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

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