دورية أكاديمية
The Discovery of Novel α2a Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening
| العنوان: | The Discovery of Novel α2a Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening |
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| المؤلفون: | Peilan Zhou, Fengfeng Lu, Huili Zhu, Beibei Shi, Xiaoxuan Wang, Shiyang Sun, Yulei Li, Ruibin Su |
| المصدر: | International Journal of Molecular Sciences, Vol 25, Iss 13, p 7233 (2024) |
| بيانات النشر: | MDPI AG, 2024. |
| سنة النشر: | 2024 |
| المجموعة: | LCC:Biology (General) LCC:Chemistry |
| مصطلحات موضوعية: | α2A adrenergic receptor, virtual screening, Gαi/o proteins, Biology (General), QH301-705.5, Chemistry, QD1-999 |
| الوصف: | Most α2-AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α2A/2B-AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α2A-AR agonists, we performed virtual screening for human α2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity. Compound P300–2342 and its three analogs significantly decreased the locomotor activity of mice (p < 0.05). Furthermore, P300–2342 and its three analogs inhibited the binding of [3H] Rauwolscine with IC50 values of 7.72 ± 0.76 and 12.23 ± 0.11 μM, respectively, to α2A-AR and α2B-AR. In α2A-AR-HEK293 cells, P300–2342 decreased forskolin-stimulated cAMP production without increasing cAMP production, which indicated that P300–2342 activated α2A-AR with coupling to the Gαi/o pathway but without Gαs coupling. P300–2342 exhibited no agonist but slight antagonist activities in α2B-AR. Similar results were obtained for the analogs of P300–2342. The docking results showed that P300–2342 formed π-hydrogen bonds with Y394, V114 in α2A-AR, and V93 in α2B-AR. Three analogs of P300–2342 formed several π-hydrogen bonds with V114, Y196, F390 in α2A-AR, and V93 in α2B-AR. We believe that these molecules can serve as leads for the further optimization of α2A-AR agonists with potentially few side effects. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1422-0067 1661-6596 |
| Relation: | https://www.mdpi.com/1422-0067/25/13/7233; https://doaj.org/toc/1661-6596; https://doaj.org/toc/1422-0067 |
| DOI: | 10.3390/ijms25137233 |
| URL الوصول: | https://doaj.org/article/413715cb6f144db08002e59c78a96389 |
| رقم الأكسشن: | edsdoj.413715cb6f144db08002e59c78a96389 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14220067 16616596 |
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| DOI: | 10.3390/ijms25137233 |