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  • Barlow, NicholasUppsala universitet,Institutionen för läkemedelskemi,Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia (author)

Macrocyclic Peptidomimetics as Inhibitors of Insulin-Regulated Aminopeptidase (IRAP)

  • Article/chapterEnglish2020

Publisher, publication year, extent ...

  • 2020
  • Royal Society of Chemistry (RSC),2020
  • printrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:uu-395288
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-395288URI
  • https://doi.org/10.1039/c9md00485hDOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • 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.

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  • Reddy Vanga, SudarsanaUppsala universitet,Beräkningsbiologi och bioinformatik(Swepub:uu)sudva502 (author)
  • Sävmarker, JonasUppsala universitet,Institutionen för läkemedelskemi (author)
  • Sandström, Anja,1973-Uppsala universitet,Läkemedelsdesign och läkemedelsutveckling(Swepub:uu)anjajoha (author)
  • Burns, PetaBiomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia (author)
  • Hallberg, Anders,1945-Uppsala universitet,Preparativ läkemedelskemi(Swepub:uu)andehall (author)
  • Åqvist, JohanUppsala universitet,Beräkningsbiologi och bioinformatik(Swepub:uu)johanaq (author)
  • Gutiérrez-de-Terán, HugoUppsala universitet,Beräkningsbiologi och bioinformatik(Swepub:uu)hugut367 (author)
  • Hallberg, Mathias,1971-Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Biologisk beroendeforskning(Swepub:uu)mha03066 (author)
  • Larhed, MatsUppsala universitet,Science for Life Laboratory, SciLifeLab,Preparativ läkemedelskemi(Swepub:uu)matslarh (author)
  • Chai, Siew YeenBiomedicine Discovery Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia (author)
  • Thompson, Philip EMedicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria 3052, Australia (author)
  • Uppsala universitetInstitutionen för läkemedelskemi (creator_code:org_t)

Related titles

  • In:RSC Medicinal chemistry: Royal Society of Chemistry (RSC)11:2, s. 234-2442632-8682

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