Dataset Information
Structural Insight into the Mechanism of 4-Aminoquinolines Selectivity for the alpha2A-Adrenoceptor.
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ABSTRACT: Background
α2A-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α2A-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α2A-AR subtype of traditional drugs greatly limits their clinic usage.Methods
A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characterized for their affinities for each α2-AR subtype. Subsequently, docking, molecular dynamics and mutagenesis were applied to uncover the molecular mechanism.Results
Most 4-aminoquinolines (4-aminoquinoline monomer, C2-C6, C8-C10) were selective for α2A-AR over α2B- and α2C-ARs. Besides, the affinities are of similar linker length-dependence for each α2-AR subtype. Among all the compounds tested, C10 has the highest affinity for α2A-AR (pKi=-7.45±0.62), which is 12-fold and 60-fold selective over α2B-AR and α2C-AR, respectively. Docking and molecular dynamics suggest that C10 simultaneously interacts with orthosteric and "allosteric" sites of the α2A-AR. The mutation of F205 decreases the affinity by 2-fold. The potential allosteric residues include S90, N93, E94 and W99.Conclusion
The specificity of C10 for the α2A-AR and the potential orthosteric and allosteric binding sites proposed in this study provide valuable guidance for the development of novel α2A-AR subtype selective compounds.
SUBMITTER: Li Z
PROVIDER: S-EPMC7340475 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
Structural Insight into the Mechanism of 4-Aminoquinolines Selectivity for the alpha2A-Adrenoceptor.
Drug design, development and therapy 20200703
<h4>Background</h4>α<sub>2A</sub>-adrenoceptor (AR) is a potential target for the treatment of degenerative diseases of the central nervous system, and α<sub>2A</sub>-AR agonists are effective drugs for this condition. However, the lack of high selectivity for α<sub>2A</sub>-AR subtype of traditional drugs greatly limits their clinic usage.<h4>Methods</h4>A series of homobivalent 4-aminoquinolines conjugated by two 4-aminoquinoline moieties via varying alkane linker length (C2-C12) were characte ...[more]