Macrocyclic peptidomimetics as inhibitors of insulin-regulated aminopeptidase (IRAP). Issue 2 (8th January 2020)

• Record Type: Journal Article
• Authors: Barlow, Nicholas; Vanga, Sudarsana Reddy; Sävmarker, Jonas; Sandström, Anja; Burns, Peta; Hallberg, Anders; Åqvist, Johan; Gutiérrez-de-Terán, Hugo; Hallberg, Mathias; Larhed, Mats; Chai, Siew Yeen; Thompson, Philip E.
• Is Part Of: MedChemComm. Volume 11:Issue 2(2020)
• Page Start: 234
• Page End: 244
• Publication Date: 2020-01-08
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19
• DOI: 10.1039/c9md00485h
• Languages: English
• ISSNs: 2040-2503

Abstract

Abstract : The IRAP inhibition of the macrocyclic peptide, HA-08 has been explored by analogue design coupled to molecular dynamics analysis. Abstract : 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 (Δ G ) and relative binding free energies (ΔΔ 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.