RESUMEN
It has demonstrated that glycogen synthase kinase 3ß (GSK3ß) is related to Alzheimer's disease (AD). On the basis of the world largest traditional Chinese medicine (TCM) database, a network-pharmacology-based approach was utilized to investigate TCM candidates that can dock well with multiple targets. Support vector machine (SVM) and multiple linear regression (MLR) methods were utilized to obtain predicted models. In particular, the deep learning method and the random forest (RF) algorithm were adopted. We achieved R2 values of 0.927 on the training set and 0.862 on the test set with deep learning and 0.869 on the training set and 0.890 on the test set with RF. Besides, comparative molecular similarity indices analysis (CoMSIA) was performed to get a predicted model. All of the training models achieved good results on the test set. The stability of GSK3ß protein-ligand complexes was evaluated using 100 ns of MD simulation. Methyl 3- O-feruloylquinate and cynanogenin A induced both more compactness to the GSK3ß complex and stable conditions at all simulation times, and the GSK3ß complex also had no substantial fluctuations after a simulation time of 5 ns. For TCM molecules, we used the trained models to calculate predicted bioactivity values, and the optimum TCM candidates were obtained by ranking the predicted values. The results showed that methyl 3- O-feruloylquinate contained in Phellodendron amurense and cynanogenin A contained in Cynanchum atratum are capable of forming stable interactions with GSK3ß.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Biología Computacional/métodos , Aprendizaje Profundo , Medicina Tradicional China , Bases de Datos Farmacéuticas , Composición de Medicamentos , Glucógeno Sintasa Quinasa 3/química , Glucógeno Sintasa Quinasa 3/metabolismo , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Conformación Proteica , Mapas de Interacción de Proteínas , Relación Estructura-Actividad Cuantitativa , Máquina de Vectores de SoporteRESUMEN
We developed a novel strategy by oxidation-derivatization combined mass spectrometry analysis for the determination of 5-hydroxymethylcytosine and 5-formylcytosine in both DNA and RNA. We reported the presence of 5-formylcytosine in RNA of mammals and found that ascorbic acid and hydroquinone can increase the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine in DNA and RNA.
