Computational Drug Design
344 Pages
English

Computational Drug Design

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Description

Helps you choose the right computational tools and techniques to meet your drug design goals

Computational Drug Design covers all of the major computational drug design techniques in use today, focusing on the process that pharmaceutical chemists employ to design a new drug molecule. The discussions of which computational tools to use and when and how to use them are all based on typical pharmaceutical industry drug design processes.

Following an introduction, the book is divided into three parts:

  • Part One, The Drug Design Process, sets forth a variety of design processes suitable for a number of different drug development scenarios and drug targets. The author demonstrates how computational techniques are typically used during the design process, helping readers choose the best computational tools to meet their goals.

  • Part Two, Computational Tools and Techniques, offers a series of chapters, each one dedicated to a single computational technique. Readers discover the strengths and weaknesses of each technique. Moreover, the book tabulates comparative accuracy studies, giving readers an unbiased comparison of all the available techniques.

  • Part Three, Related Topics, addresses new, emerging, and complementary technologies, including bioinformatics, simulations at the cellular and organ level, synthesis route prediction, proteomics, and prodrug approaches.

The book's accompanying CD-ROM, a special feature, offers graphics of the molecular structures and dynamic reactions discussed in the book as well as demos from computational drug design software companies.

Computational Drug Design is ideal for both students and professionals in drug design, helping them choose and take full advantage of the best computational tools available.

Note: CD-ROM/DVD and other supplementary materials are not included as part of eBook file.

Subjects

Informations

Published by
Published 28 January 2009
Reads 1
EAN13 9780470451847
License: All rights reserved
Language English

Legal information: rental price per page €. This information is given for information only in accordance with current legislation.

CONTENTS
PREFACE ACKNOWLEDGMENTS ABOUT THE AUTHOR SYMBOLS USED IN THIS BOOK BOOK ABSTRACT
1
Introduction 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
2
Properties that Make a Molecule a Good Drug 2.1 Compound Testing, 10 2.1.1 Biochemical Assays, 11 2.1.2 CellBased Assays, 13
xv xix xxi xxiii xxix
1
7
9
vii
viii
3
4
5
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
Target Identification 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
Target Characterization 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
The Drug Design Process for a Known Protein Target 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
41
47
53
6
7
8
The Drug Design Process for an Unknown Target 6.1 The LigandBased Design Process, 71 6.2 Initial Hits, 72 6.3 Compound Refinement, 73 6.4 ADMET, 74 Bibliography, 74
Drug Design for Other Targets 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
Compound Library Design 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
9
CONTENTS
Homology Model Building 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
ix
71
75
87
103
105
x
10
11
12
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
Molecular Mechanics 10.1 A Really Brief Introduction to Molecular Mechanics, 119 10.2 Force Fields for Drug Design, 121 Bibliography, 123
Protein Folding 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
Docking 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
119
125
133
13
14
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16
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
CONTENTS
Pharmacophore Models 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
QSAR 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
3DQSAR 15.1 The 3DQSAR Process, 182 15.2 3DQSAR Software Packages, 184 15.3 Summary, 184 Bibliography, 184
Quantum Mechanics in Drug Design 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
xi
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171
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xii
17
18
19
20
21
CONTENTS
De novoand Other AI Techniques 17.1De novoBuilding of Compounds, 198 17.2 Nonquantitative Predictions, 201 17.3 Quantitative Predictions, 203 Bibliography, 205
Cheminformatics 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
ADMET 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
Multiobjective Optimization Bibliography, 240
Automation of Tasks 21.1 BuiltIn Automation Capabilities, 241 21.2 Automation Using External Utilities, 243 Bibliography, 244
PART III
22
RELATED TOPICS
Bioinformatics Bibliography, 251
197
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23
24
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26
27
Simulations at the Cellular and Organ Level 23.1 Cellular Simulations, 253 23.2 Organ Simulations, 256 Bibliography, 256
Synthesis Route Prediction Bibliography, 262
Proteomics Bibliography, 264
Prodrug Approaches Bibliography, 270
CONTENTS
Future Developments in Drug Design 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
GLOSSARY
INDEX
xiii
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301