Computational drug design: a guide for computational and medicinal chemists
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| Main Author: | |
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| Format: | Book |
| Language: | English |
| Published: |
Hoboken, NJ
Wiley
2009
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| Subjects: | |
| Online Access: | Inhaltsverzeichnis |
| Item Description: | Includes bibliographical references and index |
| Physical Description: | XXXVI, 307 S. Ill. 1 CD-ROM (12 cm) |
| ISBN: | 9780470126851 047012685X |
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| 650 | 4 | |a Drug Delivery Systems | |
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| adam_text | Titel: Computational drug design
Autor: Young, David C.
Jahr: 2009
CONTENTS
PREFACE xv
ACKNOWLEDGMENTS xix
ABOUT THE AUTHOR xxi
SYMBOLS USED IN THIS BOOK xxiii
BOOK ABSTRACT xxix
1 Introduction 1
1.1 A Difficult Problem, 1
1.2 An Expensive Problem, 2
1.3 Where Computational Techniques are Used, 3
Bibliography, 5
PART I THE DRUG DESIGN PROCESS 7
2 Properties that Make a Molecule a Good Drug 9
2.1 Compound Testing, 10
2.1.1 Biochemical Assays, 11
2.1.2 Cell-Based Assays, 13
vii
viii CONTENTS
2.1.3 Animal Testing, 14
2.1.4 Human Clinical Trials, 15
2.2 Molecular Structure, 16
2.2.1 Activity, 16
2.2.2 Bioavailability and Toxicity, 24
2.2.3 Drug Side Effects, 26
2.2.4 Multiple Drug Interactions, 26
2.3 Metrics for Drug-Likeness, 27
2.4 Exceptions to the Rules, 33
Bibliography, 35
3 Target Identification 41
3.1 Primary Sequence and Metabolic Pathway, 41
3.2 Crystallography, 43
3.3 2D NMR, 44
3.4 Homology Models, 45
3.5 Protein Folding, 45
Bibliography, 46
4 Target Characterization 47
4.1 Analysis of Target Mechanism, 47
4.1.1 Kinetics and Crystallography, 48
4.1.2 Automated Crevice Detection, 48
4.1.3 Transition Structures and Reaction
Coordinates, 49
4.1.4 Molecular Dynamics Simulations, 49
4.2 Where the Target is Expressed, 50
4.3 Pharmacophore Identification, 50
4.4 Choosing an Inhibitor Mechanism, 51
Bibliography, 52
5 The Drug Design Process for a Known Protein Target 53
5.1 The Structure-Based Design Process, 53
5.2 Initial Hits, 55
5.3 Compound Refinement, 56
5.4 ADMET, 67
5.5 Drug Resistance, 67
Bibliography, 68
CONTENTS ix
6 The Drug Design Process for an Unknown Target 71
6.1 The Ligand-Based Design Process, 71
6.2 Initial Hits, 72
6.3 Compound Refinement, 73
6.4 ADMET, 74
Bibliography, 74
7 Drug Design for Other Targets 75
7.1 DNA Binding, 76
7.2 RNA as a Target, 78
7.3 Allosteric Sites, 79
7.4 Receptor Targets, 80
7.5 Steroids, 81
7.6 Targets inside Cells, 82
7.7 Targets within the Central Nervous System, 83
7.8 Irreversibly Binding Inhibitors, 84
7.9 Upregulating Target Activity, 84
Bibliography, 85
8 Compound Library Design 87
8.1 Targeted Libraries versus Diverse Libraries, 87
8.2 From Fragments versus from Reactions, 89
8.3 Non-Enumerative Techniques, 90
8.4 Drug-Likeness and Synthetic Accessibility, 91
8.5 Analyzing Chemical Diversity and Spanning
known Chemistries, 93
8.6 Compound Selection Techniques, 96
Bibliography, 99
PART II COMPUTATIONAL TOOLS
AND TECHNIQUES 103
9 Homology Model Building 105
9.1 How much Similarity is Enough?, 106
9.2 Steps for Building a Homology Model, 107
9.2.1 Step 1: Template Identification, 108
9.2.2 Step 2: Alignment between the Unknown and
the Template, 108
X CONTENTS
9.2.3 Step 3: Manual Adjustments to the Alignment, 110
9.2.4 Step 4: Replace Template Side Chains with Model
Side Chains, 111
9.2.5 Step 5: Adjust Model for Insertions and Deletions, 111
9.2.6 Step 6: Optimization of the Model, 112
9.2.7 Step 7: Model Validation, 112
9.2.8 Step 8: If Errors are Found, Iterate Back to
Previous Steps, 115
9.3 Reliability of Results, 116
Bibliography, 117
10 Molecular Mechanics 119
10.1 A Really Brief Introduction to Molecular Mechanics, 119
10.2 Force Fields for Drug Design, 121
Bibliography, 123
11 Protein Folding 125
11.1 The Difficulty of the Problem, 125
11.2 Algorithms, 127
11.3 Reliability of Results, 129
11.4 Conformational Analysis, 130
Bibliography, 131
12 Docking 133
12.1 Introduction, 133
12.2 Search Algorithms, 135
12.2.1 Searching the Entire Space, 135
12.2.2 Grid Potentials versus Full Force Field, 137
12.2.3 Flexible Active Sites, 138
12.2.4 Ligands Covalently Bound to the Active Site, 138
12.2.5 Hierarchical Docking Algorithms, 139
12.3 Scoring, 141
12.3.1 Energy Expressions and Consensus Scoring, 141
12.3.2 Binding Free Energies, 141
12.3.3 Solvation, 144
12.3.4 Ligands Covalently Bound to the Active Site, 144
12.3.5 Metrics for Goodness of Fit, 144
12.4 Validation of Results, 145
12.5 Comparison of Existing Search and Scoring Methods, 146
12.6 Special Systems, 153
CONTENTS xi
12.7 The Docking Process, 155
12.7.1 Protein Preparation, 156
12.7.2 Building the Ligand, 156
12.7.3 Setting the Bounding Box, 157
12.7.4 Docking Options, 157
12.7.5 Running the Docking Calculation, 158
12.7.6 Analysis of Results, 158
Bibliography, 159
13 Pharmacophore Models 161
13.1 Components of a Pharmacophore Model, 163
13.2 Creating a Pharmacophore Model from
Active Compounds, 164
13.3 Creating a Pharmacophore Model from the Active Site, 166
13.4 Searching Compound Databases, 167
13.5 Reliability of Results, 168
Bibliography, 169
14 QSAR 171
14.1 Conventional QSAR versus 3D-QSAR, 171
14.2 The QSAR Process, 172
14.3 Descriptors, 175
14.4 Automated QSAR Programs, 176
14.5 QSAR versus Other Fitting Methods, 177
Bibliography, 178
15 3D-QSAR 181
15.1 The 3D-QSAR Process, 182
15.2 3D-QSAR Software Packages, 184
15.3 Summary, 184
Bibliography, 184
16 Quantum Mechanics in Drug Design 187
16.1 Quantum Mechanics Algorithms and Software, 188
16.2 Modeling Systems with Metal Atoms, 191
16.3 Increased Accuracy, 191
16.4 Computing Reaction Paths, 193
16.5 Computing Spectra, 193
Bibliography, 194
xii CONTENTS
17 De novo and Other AI Techniques 197
17.1 De novo Building of Compounds, 198
17.2 Nonquantitative Predictions, 201
17.3 Quantitative Predictions, 203
Bibliography, 205
18 Cheminformatics 207
18.1 Smiles, SLN, and Other Chemical Structure
Representations, 208
18.2 Similarity and Substructure Searching, 209
18.3 2D-to-3D Structure Generation, 213
18.4 Clustering Algorithms, 214
18.5 Screening Results Analysis, 217
18.6 Database Systems, 222
Bibliography, 223
19 ADMET 225
19.1 Oral Bioavailability, 227
19.2 Drug Half-Life in the Bloodstream, 229
19.3 Blood-Brain Barrier Permeability, 231
19.4 Toxicity, 231
Bibliography, 234
20 Multiobjective Optimization 237
Bibliography, 240
21 Automation of Tasks 241
21.1 Built-in Automation Capabilities, 241
21.2 Automation Using External Utilities, 243
Bibliography, 244
PART ID RELATED TOPICS 245
22 Bioinformatics 247
Bibliography, 251
CONTENTS xiii
23 Simulations at the Cellular and Organ Level 253
23.1 Cellular Simulations, 253
23.2 Organ Simulations, 256
Bibliography, 256
24 Synthesis Route Prediction 259
Bibliography, 262
25 Proteomics 263
Bibliography, 264
26 Prodrug Approaches 267
Bibliography, 270
27 Future Developments in Drug Design 273
27.1 Individual Patient Genome Sequencing, 273
27.2 Analysis of the Entire Proteome, 274
27.3 Drugs Customized for Ethnic Group or Individual
Patient, 274
27.4 Genetic Manipulation, 275
27.5 Cloning, 276
27.6 Stem Cells, 277
27.7 Longevity, 278
Bibliography, 279
Appendix: About the CD 281
GLOSSARY 285
INDEX 301
|
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| spelling | Young, David C. Verfasser aut Computational drug design a guide for computational and medicinal chemists David C. Young Hoboken, NJ Wiley 2009 XXXVI, 307 S. Ill. 1 CD-ROM (12 cm) txt rdacontent n rdamedia nc rdacarrier Includes bibliographical references and index CAD gtt Computermodellen gtt Dataprocessing gtt Geneesmiddelen gtt Ontwerpen gtt Datenverarbeitung Mathematisches Modell Drugs Design Mathematical models Drugs Design Data processing Computational Biology methods Drug Design Biochemical Phenomena Chemistry, Pharmaceutical methods Drug Delivery Systems Models, Chemical Arzneimitteldesign (DE-588)4278218-1 gnd rswk-swf Arzneimitteldesign (DE-588)4278218-1 s DE-604 HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=017629751&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Young, David C. Computational drug design a guide for computational and medicinal chemists CAD gtt Computermodellen gtt Dataprocessing gtt Geneesmiddelen gtt Ontwerpen gtt Datenverarbeitung Mathematisches Modell Drugs Design Mathematical models Drugs Design Data processing Computational Biology methods Drug Design Biochemical Phenomena Chemistry, Pharmaceutical methods Drug Delivery Systems Models, Chemical Arzneimitteldesign (DE-588)4278218-1 gnd |
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| title | Computational drug design a guide for computational and medicinal chemists |
| title_auth | Computational drug design a guide for computational and medicinal chemists |
| title_exact_search | Computational drug design a guide for computational and medicinal chemists |
| title_full | Computational drug design a guide for computational and medicinal chemists David C. Young |
| title_fullStr | Computational drug design a guide for computational and medicinal chemists David C. Young |
| title_full_unstemmed | Computational drug design a guide for computational and medicinal chemists David C. Young |
| title_short | Computational drug design |
| title_sort | computational drug design a guide for computational and medicinal chemists |
| title_sub | a guide for computational and medicinal chemists |
| topic | CAD gtt Computermodellen gtt Dataprocessing gtt Geneesmiddelen gtt Ontwerpen gtt Datenverarbeitung Mathematisches Modell Drugs Design Mathematical models Drugs Design Data processing Computational Biology methods Drug Design Biochemical Phenomena Chemistry, Pharmaceutical methods Drug Delivery Systems Models, Chemical Arzneimitteldesign (DE-588)4278218-1 gnd |
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