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This study centered on cannabinoid receptors (CNRs) and aimed to screen small molecular compounds associated with flavonoids and phenolic acids derived from Tianma (Gastrodiae Rhizoma) and Fuzi (Aconiti Radix Lateralis Praeparata) for the treatment of rheumatoid arthritis (RA) through molecular docking and surface plasmon resonance (SPR) techniques. Based on the obtained results, the differences in the binding affinities of these compounds to CNR1 or CNR2 were compared.
Three flavonoids and phenolic acids, namely daidzin, daidzein and curcumin, were identified from Tianma (Gastrodiae Rhizoma) and Fuzi (Aconiti Radix Lateralis Praeparata) using a nontargeted UPLCMS metabolomics approach, which were confirmed as small molecular ligands. Subsequently, the molecular docking was employed to predict the binding modes between these compounds and CNRs. Their pharmacokinetic properties, toxicity profiles and drug-likeness were further predicted using relevant bioinformatics methods. The differences in the binding stabilities of these compounds to CNR1 or CNR2 were evaluated through molecular dynamics simulations. Finally, the stabilities of the complexes formed between the three flavonoids and phenolic acids and CNR1 (or CNR2) were verified by SPR.
The findings from molecular docking and molecular dynamics simulations demonstrated that the stabilities of the daidzin-CNR2, daidzein-CNR2 and curcumin-CNR2 complexes were higher than those of the daidzin-CNR1, daidzein-CNR1 and curcumin-CNR1 complexes, respectively. Further SPR results indicated that the dissociation constant value of the daidzin-CNR2 complex (10.19 μmol) was lower than that of the daidzin-CNR1 complex (19.67 μmol), suggesting a higher affinity of the daidzin-CNR2 complex compared to the daidzin-CNR1 complex.
The compound daidzin from Tianma (Gastrodiae Rhizoma) and Fuzi (Aconiti Radix Lateralis Praeparata), which was stably bound to CNR2, was reconfirmed via high-throughput biological informatic approach and SPR experiment. These results offer new perspectives for the application of Tianma (Gastrodiae Rhizoma) and Fuzi (Aconiti Radix Lateralis Praeparata) in the treatment of RA.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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