利用生物資訊方法分析非類固醇抗發炎藥物潛在的脫靶效應及其與阿茲海默症的關聯

Computational analysis of potential off-target effects for non-steroidal anti-inflammatory drugs and their associations with Alzheimer's disease

郭伊玹(Yi-Hsuan Kuo)

指導教授 ： 童俊維

高雄醫學大學/藥學院/藥學系碩士在職專班/碩士(2016年)

摘要

非類固醇抗炎藥物(Non-steroidal Anti-inflammatory Drugs；簡稱NSAIDs)這大類的藥品有著相似的治療活性和藥理作用機制，但每個藥物之間卻存在著很多不同的生理性差異。NSAIDs可用來緩解許多發炎疾病及疼痛，如類風濕性關節炎，但NSAIDs也可能導致許多嚴重的副作用，如胃潰瘍、胃出血、增加心血管疾病發生風險。進一步探討NSAIDs的脫靶效應將能幫助了解其副作用。這次研究目的希望找出所臨床常用類固醇抗炎藥物，利用ChemDIS (A Chemical-disease inference System based on Chemical-protein Interactions) 這個系統研究這類型的藥物的交互作用基因，並系統性分析藥物可能影響的功能、路徑與疾病，以系統藥物學研究來了解非類固醇抗炎藥物的脫靶效應，同時探討NSAIDs與阿茲海默症的關聯。
本篇研究採In silico的研究方法，來研究NSAIDs類藥物之交互作用蛋白質。利用ChemDIS系統研究NSAIDs交互作用基因和NSAIDs可能影響的功能、路徑與疾病。搜尋現有相關研究文獻數量，文獻回顧分析NSAIDs現行研究發展，以了解NSAIDs整體藥物的系統藥物學，更進一步從機轉來探討NSAIDs和阿茲海默症的關聯性，日後可供後續設計實驗驗證。
本研究分析了3577筆NSAIDs藥物與Protein(蛋白質)的交互作用。共同交互作用的蛋白質、功能與路徑皆利用ChemDIS系統進行分析。分析NSAIDs共同影響的疾病後發現，有20種NSAIDs與心血管疾病和代謝性疾病有關，其次是腎功能系統疾病(19種藥物)。造成這些疾病的成因和NSAIDs類藥物會影響 metabolism of lipids andlLipoproteins、arachidonic acid metabolism、steroid hormone biosynthesis 等相關作用途徑有關。
在這次實驗中利用生物資訊方法分析NSAIDs系統性的藥物學，同時也探討NSAIDs在生物系統中與阿茲海默症的關係和阿茲海默症現有文獻的探討。Indomethacin、ibuprofen、naproxen、flurbiprofen、aspirin、sulindac是本次實驗中推測與阿茲海默症較有影響的NSAIDs，而藥品是否存在個別化的差異期待未來用SNPs做進一步的探討。

關鍵字

非類固醇抗炎藥物 ； 脫靶效應 ； 阿茲海默症

並列摘要

The NSAIDs (Nonsteroidal Anti-inflammatory Drugs) represent the single most crowded family of drugs sharing the same therapeutic activities and mechanism of action, but there were large interindividual variability in response to these agents. NSAIDs provide symptomatic relief of pain and inflammation associated with a variety of human disorders, including the rheumatic diseases, but NSAIDs can also cause serious side effects, including stomach ulcers, stomach bleeding and increased risk of atherothrombotic vascular events. The investigation of off-target effects of NSAIDs could provide better understanding of the adverse effects.
In this study, ChemDIS were utilized to identify the interaction proteins for NSAIDs and analyze chemical-associated Gene Ontology (GO), pathway (KEGG and Reactome) and Disease Ontology (DO and DOlite) of NSAIDs based on a hypergeometric test. At the same time, this study explored the relationship between NSAIDs and Alzheimer's Disease. A total of 3,577 proteins in humans were identified to interact with NSAIDs from ChemDIS. Common proteins, functions and pathways affected by NSAIDs were analyzed from ChemDIS. The top disease categories associated with NSAIDs were cardiovascular system disease and disease of metabolism, followed by renal function disease. NSAIDs affecting Metabolism of lipids and lipoproteins, Arachidonic acid metabolism, Steroid hormone biosynthesis and other related action pathway is relation with these diseases.
The off-target effects of NSAIDs were systematically analyzed by computational methods. The association between NSAIDs and identified Alzheimer's disease was consistent with literature. Indomethacin, Ibuprofen, Naproxen, Flurbiprofen, Aspirin, Sulindac may have beneficial effect on Alzheimer's disease. Individual effects of these NSAIDs can be further investigated by integrating SNPs information

並列關鍵字

NSAID,Non-steroidal Anti-inflammatory Drug ； Off-target Effect ； Alzheimer's Disease

參考文獻

參考文獻

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