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Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (Biologisk beroendeforskning)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational and Systems Biology.
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2016 (English)In: Molecular Pharmacology, ISSN 0026-895X, E-ISSN 1521-0111, Vol. 89, no 4, p. 413-424Article in journal (Refereed) Published
Abstract [en]

Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.

Place, publisher, year, edition, pages
2016. Vol. 89, no 4, p. 413-424
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-275166DOI: 10.1124/mol.115.102533ISI: 000370935700003PubMedID: 26769413OAI: oai:DiVA.org:uu-275166DiVA, id: diva2:899107
Funder
Swedish Research CouncilAvailable from: 2016-01-31 Created: 2016-01-31 Last updated: 2019-10-16
In thesis
1. Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2: Binding modes and mechanisms from computational methods and free energy calculations
Open this publication in new window or tab >>Non-Steroidal Anti-Inflammatory Drugs in Cyclooxygenases 1 and 2: Binding modes and mechanisms from computational methods and free energy calculations
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly used classes of drugs. They target the cyclooxygenases (COX) 1 and 2 to reduce the physiological responses of pain, fever, and inflammation. Due to their role in inducing angiogenesis, COX proteins have also been identified as targets in cancer therapies.

In this thesis, I describe computational protocols of molecular docking, molecular dynamics simulations and free energy calculations. These methods were used in this thesis to determine structure-activity relationships of a diverse set of NSAIDs in binding to their target proteins COX-1 and 2. Binding affinities were calculated and used to predict the binding modes. Based on combinations of molecular dynamics simulations and free energy calculations, binding mechanisms of sub-classes of NSAIDs were also proposed. Two stable conformations of COX were probed to understand how they affect inhibitor affinities. Finally, a brief discussion on selectivity towards either COX isoform is discussed. These results will be useful in future de novo design and testing of third-generation NSAIDs.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2017. p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1560
Keywords
molecular dynamics simulations, binding free energy, molecular docking, cyclooxygenase, non-steroidal anti-inflammatory drugs, free energy perturbation, potentials of mean force
National Category
Pharmaceutical Biotechnology
Identifiers
urn:nbn:se:uu:diva-328478 (URN)978-91-513-0073-3 (ISBN)
Public defence
2017-11-02, B42, BMC, Husargatan 3, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2017-10-10 Created: 2017-08-23 Last updated: 2017-10-17
2. 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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Diwakarla, ShantiNylander, ErikGrönbladh, AlfhildReddy Vanga, SudarsanaShamsudin Khan, YasminGutierrez-de-Teran, HugoSävmarker, JonasAndersson, HannaEngen, KarinRosenström, UlrikaLarhed, MatsÅqvist, JohanHallberg, Mathias

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Diwakarla, ShantiNylander, ErikGrönbladh, AlfhildReddy Vanga, SudarsanaShamsudin Khan, YasminGutierrez-de-Teran, HugoSävmarker, JonasAndersson, HannaEngen, KarinRosenström, UlrikaLarhed, MatsÅqvist, JohanHallberg, Mathias
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