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1.
Chem Biodivers ; 19(7): e202200218, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35689671

RESUMO

Three new alkamides, achilleamide B-D (1-3) along with five known alkamides (4-8) were isolated from the aerial parts of Achillea alpina L. Structures were elucidated by spectroscopic analysis. Modified Mosher's method and electronic circular dichroism (ECD) calculations were introduced for the absolute configuration of 3. The neuroprotective effects of all the compounds were evaluated by 6-hydroxydopamine (6-OHDA)-induced cell death in human neuroblastoma SH-SY5Y cells, with concentration for 50 % of maximal effect (EC50 ) values of 3.16-24.75 µM, and the structure-activity relationship was conducted.


Assuntos
Achillea , Neuroblastoma , Fármacos Neuroprotetores , Achillea/química , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/química , Componentes Aéreos da Planta/química
2.
Biochem Biophys Res Commun ; 508(3): 709-714, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30528237

RESUMO

Phosphoinositide-3-kinase-δ (PI3Kδ) is a key regulator in the process of IgE mediated mast cell degranulation, which directly induces allergic diseases, such as asthma. This study is aimed at discovery of natural PI3Kδ inhibitors from Chinese medicine and evaluating their anti-mast cell degranulation activity. A combined virtual screening based on 3D pharmacophore model and molecular docking was used to screen for bioactive ingredients directly targeting PI3Kδ. Then, an in vitro kinase inhibition assay was conducted to evaluate the PI3Kδ inhibitory activity of the virtual screening hits. Subsequently, a ß-hexosaminidase release assay was performed to verify the anti-mast cell degranulation activity of the active compounds. Finally, ginkgoneolic acid was identified as a PI3Kδ inhibitor (IC50 = 2.49 µM) and exhibited anti-mast cell degranulation activity in vitro (IC50 = 2.40 µM). Docking studies showed that Glu826, Val827 and Val828 were key amino acid residues for PI3Kδ inhibitory activity. Ginkgoneolic acid may be a potential lead compound for developing effective and safe PI3Kδ-inhibiting drugs.


Assuntos
Bioensaio , Avaliação Pré-Clínica de Medicamentos , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/farmacologia , Interface Usuário-Computador , Animais , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Mastócitos/efeitos dos fármacos , Mastócitos/fisiologia , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/química , Ratos
3.
Mol Med Rep ; 17(1): 388-393, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29115449

RESUMO

Phosphodiesterase 10A (PDE10A) has been confirmed to be an important target for the treatment of central nervous system (CNS) disorders. The purpose of the present study was to identify PDE10A inhibitors from herbs used in traditional Chinese medicine. Pharmacophore and molecular docking techniques were used to virtually screen the chemical molecule database of Sophora flavescens, a well­known Chinese herb that has been used for improving mental health and regulating the CNS. The pharmacophore model generated recognized the common functional groups of known PDE10A inhibitors. In addition, molecular docking was used to calculate the binding affinity of ligand­PDE10A interactions and to investigate the possible binding pattern. Virtual screening based on the pharmacophore model and molecular docking was performed to identify potential PDE10A inhibitors from S. flavescens. The results demonstrated that nine hits from S. flavescens were potential PDE10A inhibitors, and their biological activity was further validated using literature mining. A total of two compounds were reported to inhibit cyclic adenosine monophosphate phosphodiesterase, and one protected against glutamate­induced oxidative stress in the CNS. The remaining six compounds require further bioactivity validation. The results of the present study demonstrated that this method was a time­ and cost­saving strategy for the identification of bioactive compounds from traditional Chinese medicine.


Assuntos
Simulação de Acoplamento Molecular , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Raízes de Plantas/química , Sophora/química , Simulação por Computador , Bases de Dados de Compostos Químicos , Avaliação Pré-Clínica de Medicamentos , Humanos , Ligantes , Conformação Molecular , Diester Fosfórico Hidrolases/química
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