實驗室關主題 > 研究生論文

亞洲大學/生物資訊/94/碩士-陳勇瑞-禽流感病毒抑制劑之虛擬藥物篩選

(1/1)

admin:
出版年: 94 
研究生: 陳勇瑞 
研究生(英文姓名): Chen, Yung-Jui 
論文名稱:  禽流感病毒抑制劑之虛擬藥物篩選
 
英文論文名稱: Identification of potent small molecule inhibitor of avian influenza A (H5N1) virus
 
指導教授: 朱學亭 
指導教授(英文姓名):  Chu, Hsueh-Ting 
學位類別:  碩士
校院名稱:  亞洲大學 
系所名稱:  生物資訊研究所
學號:  93242017 
學年度:  94 
語文別:  英文 
論文頁數:  46 
關鍵詞:  H5N1 ; 血液凝集素(HA) ; 演化分析 ; 虛擬篩選 ; 分子對接 
英文關鍵詞:  H5N1 ; Hemagglutinin ; evolutionary analysis ;
virtual screening ; docking 
被引用次數:  0
[ 摘要 ] 
過去這幾年流行性感冒在世界許多地區爆發大規模的疫情。所謂的禽流感(Avian influenza, AI)是由A型流行性感冒病毒所引起的疾病,致死率較一般流行性感冒為高。流感病毒依據病毒表面醣蛋白可區分為16種HA以及9種NA亞型。回顧過去,高病原性家禽流行性感冒(HPAI)的爆發多是源自低病原性H5或H7病毒突變而產生的。因為病毒每年皆會不斷突變,倘若禽流感病毒與其他人類流感病毒混合突變,進而演變為人傳人(Person-to-Person Transmission of Avian Influenza A)的新型流感病毒,將恐爆發大規模流行而導致數百萬人死亡。
流感病毒的表面醣蛋白Hemagglutinin (HA)和人類唾液酸(sialic acid) 的結合是病毒入侵人體的啟始步驟。因此,為了能了解流感病毒的致病力,我們分析病毒的HA蛋白結構。唾液酸sialic acid是人類呼吸道上體外面非常重要的抗原。HA蛋白和sialic acid結合的親合力影響病毒是否能入侵我們的上呼吸道。因此,HA蛋白受體接合位置的演化突變,可能導致HA蛋白對sialic acid親合活性的改變,而爆發大規模禽流感疫情。
為了瞭解禽流感HA蛋白過去演化的軌跡以預測未來可能的突變,我們從Swiss-Prot蛋白資料庫選取了82條禽流感H5N1 HA胺基酸序列進行演化速率分歧及特異性位置的分析,分析結果顯示,在1996-2005演化過程,我們找到2個specificity-determining positions (SDPs);在不同國家病毒株間的演化,則有3個分數較高的SDPs。由HA蛋白上這些活性作用位置,我們希望能尋找可以做為可能的流感藥物的先導化合物(lead compound)。我們利用利用分子對接程式GOLD對Maybridge分子資料庫進行虛擬篩選(virtual screening)。實驗結果從Maybridge資料庫中的59284個化合物中篩選出2個有可能成為禽流感病毒先導藥物的化合物。其中的(diaminoBLAHyl)-naphthalen-4-yl-methanone和禽流感HA蛋白有最高的親合力,最有可能成為治療新型流感藥物的先導化合物。 
[ 英文摘要 ] 
In recent years, outbreaks of avian influenza rapidly spread around the world. Avian influenza (AI) was caused by Type-A influenza virus. According to viral sur-face glycoprotein, there have been identified sixteen HA subtypes (H1-H16) and nine NA subtypes (N1-N9). Reviewing the revolution history of avian influenza, most of so-called highly pathogenic avian influenza (HPAI) outbreaks were originated from low virulent H5 or H7 viruses, and then mutated into high pathogenic ones. The muta-tion of influenza virus occurred such that many new virus strains were discovered each year. The recombination of different types of avian influenza virus occurs so fre-quently that human might be infected someday soon. The possible pandemic of novel influenza could cause millions of death finally.
It is the first step of viral infection the binding event between surface glycopro-tein Hemagglutinin (HA) and Sialic acid on host cell surface receptors. In the litera-ture, it was shown that the binding specificity of hemagglutinin (HA) receptor of the influenza virus could be changed only by a single amino acid substitution. As a result, the change of binding specificity between hemagglutinin and its receptor may raise its pathogenicity, and then it might trigger a possible influenza pandemic.
In this paper, we investigated 82 hemagglutinin sequences of H5N1 influenza vi-rus from Swiss-Prot protein database. We analyzed the evolutionary rates among the sequences for the investigation of possible locations where may cause the change of binding specificity. The specificity-determining positions (SDPs) in families of he-magglutinin proteins were studied. We identified two SDPs from temporal analysis within the years of 1996-2005, and three SDPs from spatial analysis between different regions.
Moreover, we endeavored to investigate potential drugs for avian influenza. We targeted the specific sites from previous sequence analysis as possible pharmacophore. Then the sites were used to find lead compounds for pharmaceutical purpose with re-ceptor-based structural analysis. We used the docking tool, GOLD, to select potential lead compounds from the Maybridge database. After screening 59284 objects in the database, two potential molecules were selected as lead compounds. The compound, (diaminoBLAHyl)-naphthalen-4-yl-methanone, is the top molecule according to the affinity with the HA protein.
 
[ 論文目次 ] 
摘 要 i
ABSTRACT ii
CONTENTS iii
誌 謝 v
LIST OF FIGURES vi
LIST OF TABLES vii
CHAPTER 1 INTRODUCTION 1
1.1 STATEMENT OF THE PROBLEM 1
1.2 RESEARCH OBJECTIVES 1
1.3 APPROACH TO THE PROBLEM 2
1.4 SCOPE OF STUDY 3
1.5 ORGANIZATION 3
CHAPTER 2 LITERATURE REVIEW 4
2.1 INFLUENZA RESEARCH 4
2.1.1 INFLUENZA BACKGROUND 5
2.1.2 VIRUS REPLICATION CYCLE 5
2.2 BIOINFORMATIC DATABASE SURVEY 7
2.2.1 SWISS-PROT 7
2.2.2 PROTEIN DATA BANK (PDB) 7
2.2.3 ZINC 7
2.2.4 MAYBRIDGE 7
2.3 SEQUENCE ALIGNMENT APPROACH 8
2.3.1 BLAST 8
2.3.2 MULTIPLE SEQUENCE ALIGNMENT (MSA) 8
2.4 COMPUTER-AIDED DRUG DESIGN (CADD) OVERVIEW 8
2.4.1 GOLD ALGORITHM 9
2.4.2 GOLD SCORING FUNCTION 9
CHAPTER 3 MATERIALS AND METHODS 10
3.1 PROTEIN SEQUENCE COLLECTION 11
3.1.1 BLAST ANALYSIS 11
3.1.2 PROTEIN INFORMATION COLLECTION 11
3.2 SEQUENCE ANALYSIS 11
3.3 EVOLUTIONARY ANALYSIS OF H5N1 HA PROTEIN SEQUENCE 12
3.4 SELECTION OF POTENTIAL LEAD COMPOUNDS 13
3.4.1 THE PREDICTION OF COMPOUND DATABASE 13
3.4.2 THE PREDICTION OF PROTEIN STRUCTURE 14
3.4.3 THE CALCULATING PROCESS OF VIRTUAL SCREENING 14
CHAPTER 4 RESULTS 15
4.1 THE DIVERGENCE IN H5N1 HA PROTEINS 15
4.1.1 PHYLOGENETIC TREE OF H5N1 HA PROTEINS 15
4.1.2 ACTIVE SITES OF THE DIVERGENCE 19
4.2 THE PREDICTION OF SDPS 19
4.2.1 SELECTION OF SDPS 19
4.2.2 POSSIBLE CHANGE OF RECEPTOR BINDING SPECIFICITY 20
4.3 VIRTUAL SCREENING OF LEAD COMPOUNDS 21
4.3.1 ACCURACY OF GOLD 21
4.3.2 SELECTION OF POTENTIAL COMPOUNDS 22
CHAPTER 5 DISCUSSION 25
APPENDIX A 27
APPENDIX B 35
APPENDIX C 36
REFERENCES 37 

Swiss-Prot
http://us.expasy.org/sprot/
PDB
http://www.rcsb.org/pdb/
ZINC
http://blaster.docking.org/zinc/
MAYBRIDGE
http://www.maybridge.com/

 

導覽

[0] 文章列表