Handbook of Chemoinformatics: From Data to Knowledge

Contents
Volume 1
Foreword xluii
Preface xlix
Contributors liii
Introduction 1
The Scope o f Chemoinformatics 3
Johann Casteiger
Textbook-Handbook 4
References 5
A History of Chemoinformatics 6
Peter Willett
Introduction 6
The Early Days: Representations and Structure Searching
The Early Days: Substructure Searching
Similarity Searching, Clustering, and Diversity Analysis
Searching Databases of Patents 11
Searching Databases of Reactions and Synthesis Design
Computer-aided Structure Elucidation 13
3D Substructure Searching 13
QSAR and Docking 14
Conclusions 16
References 16
Representation of Chemical Compounds 21
Introduction 23
Representation of Molecular Structures - Overview
John M. Barnard
Introduction 27
History 28

Chemical Nomenclature and Structure Representation: Algorithmic Generation and Conversion 51
SMILES - A Language for Molecules and ReactionsGraph Theory in Chemistry 103
Processing Constitutional Information 139
Canonical Numbering and Constitutional Symmetry Ring Perception 161
Topological Structure Generators 178
Cornbinatorics of Organic Molecular Structures
Representation and Manipulation of Stereochemistry
Representation of 3D Structures 231
3D Structure Generation 231
Conformational Analysis and Searching 262
Molecular Shape Analysis 302
Computer Visualization of Molecular Models - Tools for Man-Machine Communication in Molecular Science 320
Representation of Chemical Reactions 345
Reaction Classification and Knowledge Acquisition
The Data 389
Data Types 392
Quality Control and Data Analysis
Experimental Design 423
Standard Exchange Formats for Spectral Data
XML and Its Application in Chemistry
DatabasesIData Sources 491
Overview of DatabasesIData Sources 496
Bibliographic Databases 507
Databases of Chemical Structures 523
The CAS Information System: Applying Scientific Knowledge and Technology for Better Information 556
The Beilstein Database 608
Databases in Inorganic Chemistry 629
The Cambridge Structural Database (CSD) of Small Molecule Crystal Structures 645
Databases of Chemical Reactions 667
Spectroscopic Databases 700
Databases on Environmental Information 722
Patent Databases 743
Databases in Biochemistry and Molecular Biology
Chemistry on the Internet 794
Laboratory Information Management Systems (LIMS)
Searching Chemical Structures
Current State of the Art o f Markush Topological Search Systems
Similarity Searching in Chemical Structure Databases
Calculation of Physical and Chemical Data
Molecular Mechanics 920
Quantum Mechanics 947
Descriptors for Chemical Compounds 977
Topological Indices 981
Descriptors from Molecular Geometry 1004
A Hierarchy of Structure Representations
Representation of Molecular Chirality
Machine Learning Techniques in Chemistry
Multivariate Data Analysis in Chemistry
Partial Least Squares (PLS) in Cheminformatics
Neural Networks 11 67
Fuzzy Set Theory and Fuzzy Logic and Its Application to Molecular
Recognition 1216
Evolutionary Algorithms and their Applications in Chemistry

Expert Systems 1281
Prediction of Physical and Chemical Properties 1300
Quantitative Structure-Property Relationships 1314
Web-Based Calculation of Molecular Properties

Structure-Spectra Correlations 1349
Correlations between Chemical Structure and Infrared Spectra
Correlations between Chemical Structures and NMR Data
Computer-Assisted Structure Elucidation

Chemical Reactions and Synthesis Design
Computer-Assisted Synthesis Design (CASD) 1428
Computer-Assisted Synthesis Design by WODCA (CASD)

Drug Design 1508
Chernoinforrnatics and the Quest for Leads in Drug Discovery
QSAR in Drug Design 1532
Comparative Molecular Field Analysis (CoMFA)
3D- and nD-QSAR Methods 1576
High-Throughput Chemistry 1604
Molecular Diversity 1640
Pharmacophore and Drug Discovery 1687
De-Novo Design Systems 1712
The Docking Problem 1732
From Structural Genomics to Drug Design: Knowledge Discovery in Crystallographic Databases to Assist Lead Discovery and Optimization 17G9

Chemoinformatics/Bioinformatics 1789
Prediction o f Protein Structure Through Evolution
Sequence and Genome Bioinformatics 1812
Future Directions 1845
Index 1849

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Chemoinformatics Theory, Practice, and Product

Foreword ix
1. Chemoinformatics Theory 1
1.1 Chemoinformatics – What is it? 1
1.2 Chemo- versus Bio-informatics 2
1.3 Scientific Origins 4
1.4 Fundamental Concepts 4
1.4.1 Molecular descriptors and chemical spaces 4
1.4.2 Chemical spaces and molecular similarity 7
1.4.3 Molecular similarity, dissimilarity, and diversity 8
1.4.4 Modification and simplification of chemical spaces 9
1.5 Compound Classification and Selection 11
1.5.1 Cluster analysis 12
1.5.2 Partitioning 13
1.5.3 Support vector machines 16
1.6 Similarity Searching 17
1.6.1 Structural queries and graphs 17
1.6.2 Pharmacophores 18
1.6.3 Fingerprints 21
1.7 Machine Learning Methods 23
1.7.1 Genetic algorithms 23
1.7.2 Neural networks 24
1.8 Library Design 26
1.8.1 Diverse libraries 27
1.8.2 Diversity estimation 28
1.8.3 Multi-objective design 29
1.8.4 Focused libraries 29
1.9 Quantitative Structure-Activity Relationship Analysis 31
1.9.1 Model building 311.9.2 Model evaluation 32
1.9.3 3D-QSAR 33
1.9.4 4D-QSAR 34
1.9.5 Probabilistic methods 35
1.10 Virtual Screening and Compound Filtering 35
1.10.1 Biologically active compounds 35
1.10.2 Virtual and high-throughput screening 36
1.10.3 Filter functions 38
1.11 From Theory to Practice 40
1.11.1 Database design 40
1.11.2 Compound selection for medicinal chemistry 42
1.11.3 Computational hit identification 45
References 47
2. Practice and Products 51
2.1 Accelrys 51
2.2 ACD Labs 59
2.3 Barnard Chemical Information Ltd 67
2.4 BioByte 69
2.5 CambridgeSoft 73
2.6 CAS/Scifinder 80
2.7 ChemAxon 87
2.8 Chemical Computing Group 98
2.9 ChemInnovation Software 103
2.10 ChemNavigator 109
2.11 Chimera-Dock-Zinc from UCSF 112
2.12 Collaborative Drug Discovery (CDD, Inc.) 115
2.13 Daylight 123
2.14 Eidogen-Sertanty (previously Libraria) 127
2.15 Fujitsu Biosciences Group (previously Cache) 137
2.16 Genego 140
2.17 GVK-Bio 144
2.18 Hypercube 148
2.19 IDBS 152
2.20 Infochem 156
2.21 Jubilant Biosys 164
2.22 Leadscope 169
2.23 MDL 171
2.24 Milano Chemometrics and QSAR Research Group 180
2.25 Molecular Discovery 184
2.26 Molecular Networks 187
2.27 Open Eye Scientific Software 194
2.28 Planaria-Software 202
2.29 PubChem 203
2.30 PyMol 208
2.31 RasMol and Protein Explorer 211
2.32 Schrödinger, LLC 215
2.33 Scinova Technologies 223
2.34 Scitegic 226
2.35 Simulation Plus, Inc. 229
2.36 Spotfire 236
2.37 Summit PK 239
2.38 Symyx 243
2.39 TimTec 254
2.40 Tripos 259
SUBJECT APPENDICES
Drug Discovery Informatics Registration Systems
and Underlying Toolkits (Appendices 1 and 2)
Appendix 1 Drug, Molecular Registration Systems, and Chemistry Data
Cartridges 271
Appendix 2 Chemoinformatics Toolkits to Develop Applications 272
Content Databases (Appendices 3–7)
Appendix 3 Compound Availability Databases 273
Appendix 4 SAR Database 273
Appendix 5 Chemical Reaction Databases 274
Appendix 6 Patent Databases 275
Appendix 7 Other Compound and Drug Databases 275
Drug, Molecule, and Protein Visualization (Appendices 8–10)
Appendix 8 Chemical Drawing, Structure Viewing and Modeling Packages 276
Appendix 9 Data Analysis and Mining Tools 276
Appendix 10 Small Molecule – Protein Visualization Tools 277
Modeling and Algorithms (Appendices 11–17)
Appendix 11 Molecular Descriptors 278
Appendix 12 Clogp, Tpsa, and Lipinski Property Calculation Systems 279
Appendix 13 Qsar/Pharmacophore Programs 279
Appendix 14 Docking and Crystallographic Software 280
Appendix 15 Quantum Mechanics Calculations 280
Appendix 16 PK/ADME/Tox Databases and Predictors 280
Appendix 17 Multi-parameter Drug Development/Identification Software 281
Index 283

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