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Macrocyclic Peptido...
Macrocyclic Peptidomimetics as Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)
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- Barlow, Nicholas (author)
- Uppsala universitet,Institutionen för läkemedelskemi,Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
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- Reddy Vanga, Sudarsana (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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- Sävmarker, Jonas (author)
- Uppsala universitet,Institutionen för läkemedelskemi
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- Sandström, Anja, 1973- (author)
- Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling
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- Burns, Peta (author)
- Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia
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- Hallberg, Anders, 1945- (author)
- Uppsala universitet,Preparativ läkemedelskemi
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- Åqvist, Johan (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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- Gutiérrez-de-Terán, Hugo (author)
- Uppsala universitet,Beräkningsbiologi och bioinformatik
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- Hallberg, Mathias, 1971- (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Biologisk beroendeforskning
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- Larhed, Mats (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Preparativ läkemedelskemi
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- Chai, Siew Yeen (author)
- Biomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia
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- Thompson, Philip E (author)
- Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia
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(creator_code:org_t)
- 2020
- 2020
- English.
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In: RSC Medicinal chemistry. - : Royal Society of Chemistry (RSC). - 2632-8682. ; 11:2, s. 234-244
- Related links:
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https://www.ncbi.nlm...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Läkemedelskemi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medicinal Chemistry (hsv//eng)
Keyword
- Biokemi
- Biochemistry
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Barlow, Nicholas
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Reddy Vanga, Sud ...
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Sävmarker, Jona ...
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Sandström, Anja, ...
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Burns, Peta
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Hallberg, Anders ...
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show more...
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Åqvist, Johan
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Gutiérrez-de-Ter ...
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Hallberg, Mathia ...
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Larhed, Mats
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Chai, Siew Yeen
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Thompson, Philip ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medicinal Chemis ...
- Articles in the publication
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RSC Medicinal ch ...
- By the university
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Uppsala University