電腦模擬篩選無乳鏈球菌唾液酸合成酶小分子抑制劑及實驗評估

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Title:	電腦模擬篩選無乳鏈球菌唾液酸合成酶小分子抑制劑及實驗評估 In Silico Virtual Screening and Experimentally Evaluating Small-Molecule Inhibitors Against Sialic Acid Synthase of Streptococcus Agalactiae
Authors:	范浩俊
Contributors:	生物科技研究所
Keywords:	乙型鏈球菌感染唾液酸合成酶模擬篩選
Date:	2020
Issue Date:	2020-09-09 15:21:21 (UTC+8)
Abstract:	乙型鏈球菌感染會引起嬰兒敗血症、腦膜炎或腹膜炎，危及新生兒的生命。這類感染主要由母系垂直感染所引起，可以通過分娩過程中施用抗生素的方式進行預防性治療。然而近年來，已經分離出許多抵抗一線和二線抗生素的耐藥性乙型鏈球菌菌株。因此，尋找新型的藥物來對抗乙型鏈球菌感染至關重要。大多數的致病菌都具有唾液酸（一種醯化的酸性胺基壬糖）合成途徑，能使它們產生唾液酸修飾的莢膜多醣來模仿人類抗原，逃離宿主的免疫系統攻擊。本研究透過虛擬篩選來找出能抑制乙型鏈球菌的唾液酸合成的關鍵酵素「唾液酸合成酶的抑制劑」，來輔助治療乙型鏈球菌的感染。擬篩選一百萬個分子後，找出了數十個具有潛力的小分子化合物，並透過Lipinski規則篩選和以電腦計算機模擬進行ADMET測試的方法汰除了大部分的候選化合物。保留下的其中五個化合物，再通過酵素活性分析進行更深一層的評估，最後發現化合物5居有相當好的抑制能力，其IC50為21.2 µM。綜合以上，本研究利用治療乙型鏈球菌的感染藥物的新設計思路，迅速的找到了一個可能的先導化合物。 Group B Streptococcal (GBS) disease is a Streptococcus aga-lactiae infection that causes neonatal sepsis, meningitis, or peritoni-tis on infants. This life-threatening disease mainly infects through vertical infection, so intrapartum antibiotic prophylaxis is used dur-ing labor to prevent from getting this disease if S. agalactiae is de-tected in the birth canal. However, the first- and second-line antibi-otic-resistant strains of GBS have been isolated, it is crucial to find out a new antibacterial agent against them. Most of the pathogenic bacteria have a synthesis pathway of sialic acids, sialylated acidic amino nonose, in their body, which allows them to produce sialylat-ed capsular polysaccharide that mimic human’s antigen to helps them escape from host’s immune attack. Thus, blocking the key en-zyme, sialic acid synthase, in the sialic acid synthesis of S. agalac-tiae is expected to assist the treating S. agalactiae infection. 　　Several candidates were selected by virtual screening in this study. By eliminating candidates with Lipinski's rule and in silico ADMET test, five compounds were chosen to further evaluate by enzyme assay. Compound 5 was found to has inhibitory activity IC50 of 21.2 µM. In conclusion, this study used a new drug design idea against S. agalactiae infection, and provided a useable lead com-pound.
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