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Macrocyclic Peptidomimetics as Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Macrocyclic analogues of the linear hexapeptide, angiotensin IV (AngIV) have proved to be potent inhibitors of insulin-regulated aminopeptidase (IRAP, oxytocinase, EC 3.4.11.3). Along with higher affinity, macrocycles may also offer better metabolic stability, membrane permeability and selectivity, however predicting the outcome of particular cycle modifications is challenging. Here we describe the development of a series of macrocyclic IRAP inhibitors with either disulphide, olefin metathesis or lactam bridges and variations of ring size and other functionality. The binding mode of these compounds is proposed based on molecular dynamics analysis. Estimation of binding affinities (∆G) and relative binding free energies (∆∆G) with the linear interaction energy (LIE) method and free energy perturbation (FEP) method showed good general agreement with the observed inhibitory potency. Experimental and calculated data highlight the cumulative importance of an intact N-terminal peptide, the specific nature of the macrocycle, the phenolic oxygen and the C-terminal functionality.

National Category
Natural Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:uu:diva-395288OAI: oai:DiVA.org:uu-395288DiVA, id: diva2:1361729
Available from: 2019-10-16 Created: 2019-10-16 Last updated: 2019-10-16
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)
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Supervisors
Available from: 2019-11-13 Created: 2019-10-16 Last updated: 2019-11-13

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