The discovery, complex crystal structure, and recognition mechanism of a novel natural PDE4 inhibitor from Selaginella pulvinata

Huang, Yi‐You; Liu, Xin; Wu, Deyan; Tang, Gui‐Hua; Lai, Zengwei; Zheng, Xuehua; Yin, Sheng; Luo, Hai‐Bin

doi:10.1016/j.bcp.2017.01.016

Cited by 43 publications

(32 citation statements)

References 39 publications

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“…Selaginellin; selaginellins D, F, O, P, Q, S, and W; selaginpulvilins A, B, E, F, I, K, L, N, O, and T; with selariscins A, and B; and selariscinins B, and D were the unique compounds identified from both the DCM and methanolic (MeOH) extracts. Selaginellin was initially isolated from S. sinensis [31], selaginellin S from S. moellendorffii Hieron [40]; selaginellin O [33], selaginpulvilin N [36], selaginpulvilin O [36], selaginpulvilin T [36], selariscin A [36], selariscin B [36], selariscinin B [3], and selariscinin D [3] from S. tamariscina; and selaginellin D [29], selaginellin F [29], selaginellin P [30], selaginellin Q [30], selaginpulvilin A [41], selaginpulvilin B [41], selaginpulvilin E [42,43], selaginpulvilin F [43], selaginpulvilin I [43], selaginpulvilin K [44], and selaginpulvilin L [44] were isolated for the first time from S. pulvinata.…”

Section: Discussionmentioning

confidence: 99%

Comparison of Chemical Composition and Biological Activities of Eight Selaginella Species

et al. 2020

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Selaginella P. Beauv. is a group of vascular plants in the family Selaginellaceae Willk., found worldwide and numbering more than 700 species, with some used as foods and medicines. The aim of this paper was to compare methanolic (MeOH) and dichloromethane (DCM) extracts of eight Selaginella species on the basis of their composition and biological activities. Six of these Selaginella species are underinvestigated. Using ultra-high performance liquid chromatography–high-resolution mass spectrometry (UHPLC–HRMS) analysis, we identified a total of 193 compounds among the tested Selaginella species, with flavonoids predominating. MeOH extracts recovered more constituents that were detected, including selaginellins, the occurrence of which is only typical for this plant genus. Of all the tested species, Selaginellaapoda contained the highest number of identified selaginellins. The majority of the compounds were identified in S. apoda, the fewest compounds in Selaginellacupressina. All the tested species demonstrated antioxidant activity using oxygen radical absorption capacity (ORAC) assay, which showed that MeOH extracts had higher antioxidant capacity, with the half maximal effective concentration (EC50) ranging from 12 ± 1 (Selaginellamyosuroides) to 124 ± 2 (Selaginellacupressina) mg/L. The antioxidant capacity was presumed to be correlated with the content of flavonoids, (neo)lignans, and selaginellins. Inhibition of acetylcholinesterase (AChE) was mostly discerned in DCM extracts and was only exhibited in S. myosuroides, S. cupressina, Selaginellabiformis, and S. apoda extracts with the half maximal inhibitory concentration (IC50) in the range of 19 ± 3 to 62 ± 1 mg/L. Substantial cytotoxicity against cancer cell lines was demonstrated by the MeOH extract of S. apoda, where the ratio of the IC50 HEK (human embryonic kidney) to IC50 HepG2 (hepatocellular carcinoma) was 7.9 ± 0.2. MeOH extracts inhibited the production of nitrate oxide and cytokines in a dose-dependent manner. Notably, S. biformis halved the production of NO, tumor necrosis factor (TNF)-α, and interleukin (IL)-6 at the following concentrations: 105 ± 9, 11 ± 1, and 10 ± 1 mg/L, respectively. Our data confirmed that extracts from Selaginella species exhibited cytotoxicity against cancer cell lines and AChE inhibition. The activity observed in S. apoda was the most promising and is worth further exploration.

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Section: Discussionmentioning

confidence: 99%

Comparison of Chemical Composition and Biological Activities of Eight Selaginella Species

et al. 2020

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“…Then, were purified by using similar protocols as previously reported. 31,44 Enzymatic Assays. The enzymatic activities of the catalytic domain of PDE10A2 were measured with 3 H-cAMP (20,000−30,000 cpm, GE Healthcare) as the substrate in a buffer composed of 50 mM Tris, pH = 7.5, 4 mM MgCl 2 , and 1 mM dithiothreitol.…”

Section: ■ Methodsmentioning

confidence: 99%

“…The recombinant PDE10A catalytic domain (residues 449–770) was expressed and purified by using previously reported protocols. , Briefly, the plasmid (pET15b-PDE10A) was transferred to E. coli strain BL21 (Codonplus, Stratagene). Then, the E. coli cells carrying the recombinant plasmid were grown in 2XYT medium (containing 100 μg/mL ampicillin and 30 μg/mL chloramphenicol) at 37 °C until an absorption of OD 600 = 0.6–0.8.…”

Section: Methodsmentioning

confidence: 99%

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Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors

Zhang

Huang

et al. 2020

ACS Chem. Neurosci.

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Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington’s disease. Recently, a hit compound 1 with a novel chromone scaffold has shown moderate inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC50 = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t 1/2 = 105 min) by using an integrated strategy (molecular modeling, chemical synthesis, bioassay, and cocrystal structure). The cocrystal structural information provides insights into the binding pattern of 3e in the PDE10A catalytic domain to highlight the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693, respectively, thereby resulting in high selectivity against other PDEs. These new observations are of benefit for the rational design of the next generation PDE10 inhibitors for CNS disorders.

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“…S. pulvinata is used in traditional Chinese medicine for the treatment of traumatic injury and asthma (Cao et al, 2010). Pharmacological investigations revealed its various biological activities, such as anti-cancer (Wang et al, 2016) and anti-inflammatory effects (Huang et al, 2017). Unfortunately, because of its overexploitation, populations of S. pulvinata have decreased sharply.…”

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confidence: 99%

In Vitro Propagation of Resurrection Plant Selaginella pulvinata Using Frond Tips as Explants

Yu¹,

Cheng²,

Pu³

et al. 2021

horts

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The resurrection plant Selaginella pulvinata (Hook. & Grev.) Maxim is used as an ornamental and medicinal plant. It is also a good candidate for exploring the desiccation tolerance of resurrection plants. However, there is not an efficient propagation method for S. pulvinata. In the present study, we evaluated the establishment of in vitro propagation of S. pulvinata using frond tips as explants. The original shoot induction, adventitious shoot proliferation and plantlet growth media, and substrate type of plantlet acclimatization were investigated. The highest induction rate of original shoots (61.77 ± 5.17%) was obtained on half-strength (1/2) MS medium supplemented with 0.1 mg·L−1 N6-benzylaminopurine (BAP). The 1/2 MS with 1.0 mg·L−1 BAP was the most effective medium for the adventitious shoot proliferation. The quarter-strength (1/4) MS containing 0.1% (w/v) active charcoal (AC) was optimum for plantlets proliferated from adventitious shoots and plantlet growth. Approximately 98 plantlets could be obtained from one single original shoot via one-time shoot proliferation cultivation and plantlet cultivation. The acclimated plants on a 5:1 (v/v) mixture of peat and perlite had the highest survival rate (92.13 ± 1.67%). The acclimated plants maintained excellent resurrection ability.

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The discovery, complex crystal structure, and recognition mechanism of a novel natural PDE4 inhibitor from Selaginella pulvinata

Cited by 43 publications

References 39 publications

Comparison of Chemical Composition and Biological Activities of Eight Selaginella Species

Comparison of Chemical Composition and Biological Activities of Eight Selaginella Species

Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors

In Vitro Propagation of Resurrection Plant Selaginella pulvinata Using Frond Tips as Explants

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