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Modeling binding modes of angiotensin II and pseudopeptide analogues to the AT2 receptor
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry.
2008 (English)In: Journal of Molecular Graphics and Modelling, ISSN 1093-3263, Vol. 26, no 6, 991-1003 p.Article in journal (Refereed) Published
Abstract [en]

The 3D model of the AT(2) receptor has been built employing homology to the transmembrane domain of rhodopsin and a novel build-up procedure for restoring the extracellular loops. By docking a model peptide of angiotensin II in the AT(2) receptor model two plausible binding modes were identified. These binding modes were in agreement with most of the suggested ligand-receptor contact points reported in the literature. Eight active and one inactive pseuclopeptide angiotensin II analogue were also docked in the receptor and four of the active pseudopeptides were found to mimic the binding mode of angiotensin II. An alternative binding mode for the other four active pseudopeptides was found.

Place, publisher, year, edition, pages
2008. Vol. 26, no 6, 991-1003 p.
Keyword [en]
AT(2) receptor, angiotensin II, homology modeling, docking, bioactive conformation
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95770DOI: 10.1016/j.jmgm.2007.08.005ISI: 000253068700012PubMedID: 17936050OAI: oai:DiVA.org:uu-95770DiVA: diva2:170106
Available from: 2007-04-17 Created: 2007-04-17 Last updated: 2010-01-13Bibliographically approved
In thesis
1. Computational Modeling of the AT2 Receptor and AT2 Receptor Ligands: Investigating Ligand Binding, Structure–Activity Relationships, and Receptor-Bound Models
Open this publication in new window or tab >>Computational Modeling of the AT2 Receptor and AT2 Receptor Ligands: Investigating Ligand Binding, Structure–Activity Relationships, and Receptor-Bound Models
2007 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Rational conversion of biologically active peptides to nonpeptide compounds with retained activity is an appealing approach in drug development. One important objective of the work presented in this thesis was to use computational modeling to aid in such a conversion of the peptide angiotensin II (Ang II, Asp-Arg-Val-Tyr-Ile-His-Pro-Phe). An equally important objective was to gain an understanding of the requirements for ligand binding to the Ang II receptors, with a focus on interactions with the AT2 receptor.

The bioactive conformation of a peptide can provide important guidance in peptidomimetic design. By designing and introducing well-defined secondary structure mimetics into Ang II the bioactive conformation can be addressed. In this work, both γ- and β-turn mimetic scaffolds have been designed and characterized for incorporation into Ang II. Using conformational analysis and the pharmacophore recognition method DISCO, a model was derived of the binding mode of the pseudopeptide Ang II analogues. This model indicated that the positioning of the Arg side chain was important for AT2 receptor binding, which was also supported when the structure–activity relationship of Ang II was investigated by performing a glycine scan.

To further examine ligand binding, a 3D model of the AT2 receptor was constructed employing homology modeling. Using this receptor model in a docking study of the ligands, binding modes were identified that were in agreement with data from point-mutation studies of the AT2 receptor.

By investigating truncated Ang II analogues, small pseudopeptides were developed that were structurally similar to nonpeptide AT2 receptor ligands. For further guidance in ligand design of nonpeptide compounds, three-dimensional quantitative structure–activity relationship models for AT1 and AT2 receptor affinity as well as selectivity were derived.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2007. 78 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 54
Keyword
Pharmaceutical chemistry, Angiotensin II, AT1, AT2, SAR, bioactive conformation, turn mimetic, peptidomimetic, DISCO, homology model, 3D-QSAR, CoMFA, Farmaceutisk kemi
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-7823 (URN)978-91-554-6867-5 (ISBN)
Public defence
2007-05-11, B41, BMC, Husargatan 3, Uppsala, 13:15
Opponent
Supervisors
Available from: 2007-04-17 Created: 2007-04-17 Last updated: 2012-05-16Bibliographically approved

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