Abstract
Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder and the pathogenesis of AD is poorly understood. G protein-coupled receptors (GPCRs) are involved in numerous key AD pathways and play a key role in the pathology of AD. To fully understand the pathogenesis of AD and design novel drug therapeutics, analyzing the connection between AD and GPCRs is of great importance. In this paper, we firstly build and analyze the AD-related pathway by consulting the KEGG pathway of AD and a mass of literature and collect 25 AD-related GPCRs for drug discovery. Then the ILbind and AutoDock Vina tools are integrated to find out potential drugs related to AD. According to the analysis of DUD-E dataset, we select five drugs, that is, Acarbose (ACR), Carvedilol (CVD), Digoxin (DGX), NADH (NAI), and Telmisartan (TLS), by sorting the ILbind scores (≥0.73). Then depending on their AutoDock Vina scores and pocket position information, the binding patterns of these five drugs are obtained. We analyze the regulation function of GPCRs in the metabolic network of AD based on the drug screen results, which may be helpful for the study of the off-target effect and the side effect of drugs.
Highlights
Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disorder
There exist three main hypotheses for the pathogenesis of the disease: (i) cholinergic hypothesis which maintains that decreased acetylcholine (ACh) contributes to the cognitive decline commonly observed in AD [2]; (ii) amyloid hypothesis which supposes that the accumulation of amyloid-β (Aβ) is the fundamental cause of AD [3]; (iii) tau protein hypothesis which holds that the dysfunction of hyperphosphorylated microtubule-associated protein tau results in neurofibrillary lesions and initiates AD [4]
We employ the GPCR structure models predicted by GPCR-I-TASSER pipeline, which is a computational method designed for 3D structure prediction of G protein-coupled receptors, to analyze the binding site information
Summary
Alzheimer’s disease (AD) is a chronic and progressive neurodegenerative disorder. There exist three main hypotheses for the pathogenesis of the disease: (i) cholinergic hypothesis which maintains that decreased acetylcholine (ACh) contributes to the cognitive decline commonly observed in AD [2]; (ii) amyloid hypothesis which supposes that the accumulation of amyloid-β (Aβ) is the fundamental cause of AD [3]; (iii) tau protein hypothesis which holds that the dysfunction of hyperphosphorylated microtubule-associated protein tau results in neurofibrillary lesions and initiates AD [4]. Acquiring the crystal structure of a GPCR is the first step in analyzing the metabolic mechanism of GPCR in AD and further researching the binding site information related to AD. We employ the GPCR structure models predicted by GPCR-I-TASSER pipeline, which is a computational method designed for 3D structure prediction of G protein-coupled receptors, to analyze the binding site information
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