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- Malo, Marcus, et al.
(författare)
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Investigation of D1 receptor-agonist interactions and D1/D2 agonist selectivity using a combination of pharmacophore and receptor homology modelling
- 2012
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Ingår i: ChemMedChem. - : Wiley. - 1860-7179 .- 1860-7187. ; 7:3, s. 483-494
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to use a combined structure and pharmacophore modeling approach to extract information regarding dopamine D1 receptor agonism and D1/D2 agonist selectivity. A 3D structure model of the D1 receptor in its agonist-bound state was constructed with a full D1 agonist present in the binding site. Two different binding modes were identified using (+)-doxanthrine or SKF89626 in the modeling procedure. The 3D model was further compared with a selective D1 agonist pharmacophore model. The pharmacophore feature arrangement was found to be in good agreement with the binding site composition of the receptor model, but the excluded volumes did not fully reflect the shape of the agonist binding pocket. A new receptor-based pharmacophore model was developed with forbidden volumes centered on atom positions of amino acids in the binding site. The new pharmacophore model showed a similar ability to discriminate as the previous model. A comparison of the 3D structures and pharmacophore models of D1 and D2 receptors revealed differences in shape and ligand-interacting features that determine selectivity of D1 and D2 receptor agonists. A hydrogen bond pharmacophoric feature (Ser-TM5) was shown to contribute most to the selectivity. Non-conserved residues in the binding pocket that strongly contribute to D1/D2 receptor agonist selectivity were also identified; those were Ser/Cys3.36, Tyr/Phe5.38, Ser/Tyr5.41, and Asn/His6.55 in the transmembrane (TM) helix region, together with Ser/Ile and Leu/Asn in the second extracellular loop (EC2). This work provides useful information for the design of new selective D1 and D2 agonists. The combined receptor structure and pharmacophore modeling approach is considered to be general, and could therefore be applied to other ligand–protein interactions for which experimental information is limited.
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| 2. |
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| 3. |
- Malo, Marcus, et al.
(författare)
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Selective pharmacophore models of dopamine D(1) and D(2) full agonists based on extended pharmacophore features.
- 2010
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Ingår i: ChemMedChem. - : Wiley. - 1860-7187 .- 1860-7179. ; 5:2, s. 232-46
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Tidskriftsartikel (refereegranskat)abstract
- This study is focused on the identification of structural features that determine the selectivity of dopamine receptor agonists toward D(1) and D(2) receptors. Selective pharmacophore models were developed for both receptors. The models were built by using projected pharmacophoric features that represent the main agonist interaction sites in the receptor (the Ser residues in TM5 and the Asp in TM3), a directional aromatic feature in the ligand, a feature with large positional tolerance representing the positively charged nitrogen in the ligand, and sets of excluded volumes reflecting the shapes of the receptors. The sets of D(1) and D(2) ligands used for modeling were carefully selected from published sources and consist of structurally diverse, conformationally rigid full agonists as active ligands together with structurally related inactives. The robustness of the models in discriminating actives from inactives was tested against four ensembles of conformations generated by using different established methods and different force fields. The reasons for the selectivity can be attributed to both geometrical differences in the arrangement of the features, e.g., different tilt angels of the pi system, as well as shape differences covered by the different sets of excluded volumes. This work provides useful information for the design of new D(1) and D(2) agonists and also for comparative homology modeling of D(1) and D(2) receptors. The approach is general and could therefore be applied to other ligand-protein interactions for which no experimental protein structure is available.
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