<p>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 AT<sub>2</sub> receptor.</p><p>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 AT<sub>2</sub> receptor binding, which was also supported when the structure–activity relationship of Ang II was investigated by performing a glycine scan.</p><p>To further examine ligand binding, a 3D model of the AT<sub>2</sub> 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 AT<sub>2</sub> receptor.</p><p>By investigating truncated Ang II analogues, small pseudopeptides were developed that were structurally similar to nonpeptide AT<sub>2</sub> receptor ligands. For further guidance in ligand design of nonpeptide compounds, three-dimensional quantitative structure–activity relationship models for AT<sub>1</sub> and AT<sub>2</sub> receptor affinity as well as selectivity were derived. </p>
| Identifer | oai:union.ndltd.org:UPSALLA/oai:DiVA.org:uu-7823 |
| Date | January 2007 |
| Creators | Sköld, Christian |
| Publisher | Uppsala University, Organic Pharmaceutical Chemistry, Uppsala : Acta Universitatis Upsaliensis |
| Source Sets | DiVA Archive at Upsalla University |
| Language | English |
| Detected Language | English |
| Type | Doctoral thesis, comprehensive summary, text |
| Relation | Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, 1651-6192 ; 54 |
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