臺灣博碩士論文加值系統

Table of Content
口試委員會審定書......................................................................................................... i
誌謝................................................................................................................................. ii
中文摘要......................................................................................................................... iv
ABSTRACT..................................................................................................................... vi
LIST OF FIGURES........................................................................................................ xi
LIST OF TABLES.......................................................................................................... xiii
CHAPTER 1. Introduction............................................................................................. 1
1.1 Lead optimization in computer-aided drug design.......................................... 1
1.2 Computer-assisted synthesis design................................................................ 3
1.3 New methodologies of lead optimization drug design.................................... 4
1.3.1 Structure-based fragment hopping of lead optimization : LeadOp....... 5
1.3.2 Lead optimization with synthetic accessibility: LeadOp+R................. 6
1.4 Data Sets.......................................................................................................... 7
1.4.1 Mutatnt B-Raf kinase inhibitors............................................................ 8
1.4.2 Human 5-Lipoxygenase inhibitors........................................................ 9
1.4.3 Tie-2 kinase inhibitors......................................................................... 10
CHAPTER 2. LeadOp.................................................................................................... 11
2.1 Introduction of LeadOp system.................................................................. 11
2.2 Materials.................................................................................................... 12
2.3 Algorithm of LeadOp................................................................................. 12
2.3.1 Overall procedure of LeadOp............................................................. 12
2.3.2 Generation of fragments................................................................... 15
2.3.3 Pre-docked fragment database construction..................................... 15
2.3.4 Preparation for optimization............................................................. 16
2.3.5 Selection of fragments to be replaced.............................................. 16
2.3.6 Tabu Search for better replacement and compounds assembly........ 17
2.3.7 Trimming the potential compound library........................................ 17
2.3.8 Molecular dynamics simulations...................................................... 17
2.4 Result and Discussion of LeadOp............................................................ 19
2.4.1 LeadOp for mutant B-Raf kinase inhibitors..................................... 19
2.4.2 LeadOp for Human 5-lipoxygenase inhibitors................................. 28
2.5 Conclsion................................................................................................ 38
CHAPTER 3. LeadOp+R............................................................................................. 40
3.1 Introduction of LeadOp+R system.......................................................... 40
3.2 Materials................................................................................................. 41
3.3 Algorithm of LeadOp+R.......................................................................... 42
3.3.1 Overall procedure of LeadOp+R....................................................... 42
3.3.2 Constructurion of the LeadOp+R reaction database........................... 44
3.3.3 Identify reactant……………………………………………………... 48
3.3.4 Determine reaction rules for each reactant identified.......................... 48
3.3.5 Generation of reaction products based on reaction rules..................... 48
3.3.6 Evaluation of the products for each reaction....................................... 50
3.3.7 Final selection by strcture-based analysis........................................... 51
3.3.8 Molecular dynatmics simulations....................................................... 52
3.4 Result and Discussion of LeadOp+R.......................................................... 54
3.4.1 LeadOp+R optimization with for Tie-2 kinase inhibitors.................. 54
3.4.1.1 Structure-based lead optimization with synthetic routes.......... 54
3.4.1.2 Synthetic routes suggested by LeadOp+R................................ 61
3.4.2 LeadOp+R optimization with for 5-lipoxygenase inhibitors ............. 72
3.4.2.1 Structure-based lead optimization with synthetic routes.......... 72
3.4.2.2 Synthetic routes suggested by LeadOp+R................................ 78
3.5 Comparision of LeadOp and LeadOp+R in the 5-lipoxygenase system.... 91
CHAPTER 4. Conclusion............................................................................................. 93
REFERENCE................................................................................................................ 96
APPENDIX…............................................................................................................. 111

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