Virtual Screening: Principles, Challenges, and Practical GuidelinesISBN: 978-3-527-32636-5
Hardcover
550 pages
February 2011
|
List of Contributors XVII
Preface XXIII
A Personal Foreword XXV
Part One Principles 1
1 Virtual Screening of Chemical Space: From Generic Compound Collections to Tailored Screening Libraries 3
Markus Boehm
1.1 Introduction 3
1.2 Concepts of Chemical Space 4
1.3 Concepts of Druglikeness and Leadlikeness 6
1.4 Diversity-Based Libraries 8
1.4.1 Concepts of Molecular Diversity 8
1.4.2 Descriptor-Based Diversity Selection 9
1.4.3 Scaffold-Based Diversity Selection 12
1.4.4 Sources of Diversity 13
1.5 Focused Libraries 15
1.5.1 Concepts of Focused Design 15
1.5.2 Ligand-Based Focused Design 16
1.5.3 Structure-Based Focused Design 17
1.5.4 Chemogenomics Approaches 18
1.6 Virtual Combinatorial Libraries and Fragment Spaces 20
1.7 Databases of Chemical and Biological Information 21
1.8 Conclusions and Outlook 24
1.9 Glossary 25
References 26
2 Preparing and Filtering Compound Databases for Virtual and Experimental Screening 35
Maxwell D. Cummings, Éric Arnoult, Christophe Buyck, Gary Tresadern, Ann M. Vos, and Jörg K. Wegner
2.1 Introduction 35
2.2 Ligand Databases 36
2.2.1 Chemical Data Structures 36
2.2.2 3D Conformations 38
2.2.3 Data Storage 39
2.2.4 Workflow Tools 39
2.2.5 Past Reviews and Recent Papers 40
2.3 Considering Physicochemical Properties 42
2.3.1 Druglikeness 42
2.3.2 Leadlikeness and Beyond 43
2.4 Undesirables 43
2.4.1 Screening Artifacts 44
2.4.2 Pharmacologically Promiscuous Compounds 45
2.5 Property-Based Filtering for Selected Targets 46
2.5.1 Antibacterials 47
2.5.2 CNS 49
2.5.3 Protein–Protein Interactions 51
2.6 Summary 52
References 53
3 Ligand-Based Virtual Screening 61
Herbert Koeppen, Jan Kriegl, Uta Lessel, Christofer S. Tautermann, and Bernd Wellenzohn
3.1 Introduction 61
3.2 Descriptors 62
3.3 Search Databases and Queries 67
3.3.1 Selection of Reference Ligands 67
3.3.2 Preparation of the Search Database 68
3.4 Virtual Screening Techniques 68
3.4.1 Similarity Searches 69
3.4.2 Similarity Searches in Very Large Chemical Spaces 72
3.4.3 Machine Learning in Virtual Screening 74
3.4.4 Validation of Methods and Prediction of Success 78
3.5 Conclusions 79
References 80
4 The Basis for Target-Based Virtual Screening: Protein Structures 87
Jason C. Cole, Oliver Korb, Tjelvar S.G. Olsson, and John Liebeschuetz
4.1 Introduction 87
4.2 Selecting a Protein Structure for Virtual Screening 87
4.2.1 Why Are There Errors in Crystal Structures? 87
4.2.2 Possible Problems That May Occur in a Crystal Structure 91
4.2.3 Structural Relevance 95
4.2.4 Critical Evaluation of Models: Recognizing Issues in Structures 98
4.3 Setting Up a Protein Model for vHTS 101
4.3.1 Binding Site Definition 101
4.3.2 Protonation 104
4.3.3 Treatment of Solvent in Docking 104
4.3.4 Use of Protein-Based Constraints in Docking 105
4.3.5 Protein Flexibility 106
4.4 Summary 109
4.5 Glossary of Crystallographic Terms 110
4.5.1 R-Factor 110
4.5.2 Resolution 110
4.5.3 2mFo-DFc Map 110
References 110
5 Pharmacophore Models for Virtual Screening 115
Patrick Markt, Daniela Schuster, and Thierry Langer
5.1 Introduction 115
5.2 Compilation of Compounds 116
5.2.1 Chemical Structure Generation 116
5.2.2 Conformational Analysis 116
5.3 Pharmacophore Model Generation 117
5.3.1 State of the Art 117
5.3.2 Structure-Based Methods 117
5.3.3 Ligand-Based Methods 118
5.3.4 Limitations of Ligand-Based Methods 119
5.4 Validation of Pharmacophore Models 119
5.4.1 Chemical Databases for Validation 119
5.4.2 Enrichment Assessment 121
5.4.3 Enrichment Metrics 122
5.4.4 Receiver Operating Characteristic Curve Analysis 124
5.4.5 Area Under the ROC Curve 125
5.5 Pharmacophore-Based Screening 127
5.5.1 DS CATALYST 128
5.5.2 UNITY (GALAHAD/GASP) 128
5.5.3 LIGANDSCOUT 129
5.5.4 MOE 130
5.5.5 PHASE 130
5.6 Postprocessing of Pharmacophore-Based Screening Hits 131
5.6.1 Lead- and Druglikeness 131
5.6.2 Structural Similarity Analysis 131
5.7 Pharmacophore-Based Parallel Screening 132
5.8 Application Examples for Synthetic Compound Screening 133
5.8.1 17b-Hydroxysteroid Dehydrogenase 1 Inhibitors 133
5.8.2 Cannabinoid Receptor 2 (CB2) Ligands 134
5.8.3 Further Application Examples 136
5.9 Application Examples for Natural Product Screening 136
5.9.1 Cyclooxygenase (COX) Inhibitors 139
5.9.2 Sigma-1 (s1) Receptor Ligands 139
5.9.3 Acetylcholinesterase Inhibitors 140
5.9.4 Human Rhinovirus Coat Protein Inhibitors 141
5.9.5 Quorum-Sensing Inhibitors 141
5.9.6 Peroxisome Proliferator-Activated Receptor c Ligands 141
5.9.7 b-Ketoacyl-Acyl Carrier Protein Synthase III Inhibitors 142
5.9.8 5-Lipoxygenase Inhibitors 142
5.9.9 11b-Hydroxysteroid Dehydrogenase Type 1 Inhibitors 142
5.9.10 Pharmacophore-Based Parallel Screening of Natural Products 143
5.10 Conclusions 143
References 144
6 Docking Methods for Virtual Screening: Principles and Recent Advances 153
Didier Rognan
6.1 Principles of Molecular Docking 153
6.1.1 Sampling Degrees of Freedom of the Ligand 154
6.1.2 Scoring Ligand Poses 156
6.2 Docking-Based Virtual Screening Flowchart 158
6.2.1 Ligand Setup 158
6.2.2 Protein Setup 159
6.2.3 Docking 160
6.2.4 Postdocking Analysis 161
6.3 Recent Advances in Docking-Based VS Methods 162
6.3.1 Novel Docking Algorithms 162
6.3.2 Fragment Docking 164
6.3.3 Postdocking Refinement 164
6.3.4 Addressing Protein Flexibility 166
6.3.5 Solvated or Dry? 168
6.4 Future Trends in Docking 168
References 169
Part Two Challenges 177
7 The Challenge of Affinity Prediction: Scoring Functions for Structure-Based Virtual Screening 179
Christoph Sotriffer and Hans Matter
7.1 Introduction 179
7.2 Physicochemical Basis of Protein–Ligand Recognition 180
7.3 Classes of Scoring Functions 185
7.3.1 Force Field-Based Methods 185
7.3.2 Empirical Scoring Functions 189
7.3.3 Knowledge-Based Scoring Functions 191
7.4 Interesting New Approaches to Scoring Functions 192
7.4.1 Improved Treatment of Hydrophobicity and Dehydration 192
7.4.2 Development and Validation of SFCscore 194
7.4.3 Consensus Scoring 195
7.4.4 Tailored Scoring Functions 196
7.4.5 Structural Interaction Fingerprints 199
7.5 Comparative Assessment of Scoring Functions 200
7.6 Tailoring Scoring Strategies in Virtual Screening 203
7.6.1 Toward a Strategy for Applying Scoring Functions 203
7.6.2 Retrospective Validation Prior to Prospective Virtual Screening 204
7.6.3 Lessons Learned: Improvements in Scoring Evaluations 205
7.6.4 Postfiltering Results of Virtual Screenings 205
7.7 Caveats for Development of Scoring Functions 206
7.7.1 General Points 206
7.7.2 Biological Data 207
7.7.3 Structural Data on Protein–Ligand Complexes and Decoy Data Sets 207
7.7.4 Cooperativity and Other Model Deficiencies 208
7.8 Conclusions 209
References 210
8 Protein Flexibility in Structure-Based Virtual Screening: From Models to Algorithms 223
Angela M. Henzler and Matthias Rarey
8.1 How Flexible Are Proteins? – A Historical Perspective 223
8.1.1 Ligand Binding Is Coupled with Protein Conformational Change 223
8.1.2 Types of Flexibility 224
8.2 Flexible Protein Handling in Protein–Ligand Docking 225
8.2.1 Docking Following Conformational Selection 227
8.2.2 Induced Fit Docking: Single-Structure-Based Docking Techniques 231
8.2.3 Integrated Docking Approaches 235
8.3 Flexible Protein Handling in Docking-Based Virtual Screening 236
8.3.1 Efficiency of Fully Flexible Docking Approaches in Retrospective 237
8.3.2 Discrimination of Binders and Nonbinders 238
8.4 Summary 238
References 239
9 Handling Protein Flexibility in Docking and High-Throughput Docking: From Algorithms to Applications 245
Claudio N. Cavasotto
9.1 Introduction: Docking and High-Throughput Docking in Drug Discovery 245
9.2 The Challenge of Accounting for Protein Flexibility in Docking 246
9.2.1 Theoretical Understanding of the Problem 246
9.2.2 Docking Failures Due to Protein Flexibility 247
9.3 Accounting for Protein Flexibility in Docking-Based Drug Discovery and Design 250
9.3.1 Receptor Ensemble-Based Docking Methods 252
9.3.2 Single-Structure-Based Docking Methods 253
9.3.3 Multilevel Methods 256
9.3.4 Homology Modeling 257
9.4 Conclusions 257
References 258
10 Consideration of Water and Solvation Effects in Virtual Screening 263
Johannes Kirchmair, Gudrun M. Spitzer, and Klaus R. Liedl
10.1 Introduction 263
10.2 Experimental Approaches for Analyzing Water Molecules 266
10.3 Computational Approaches for Analyzing Water Molecules 271
10.3.1 Molecular Dynamics Simulations 271
10.3.2 Empirical and Implicit Considerations of Solvation Effects 274
10.4 Water-Sensitive Virtual Screening: Approaches and Applications 275
10.4.1 Protein–Ligand Docking 275
10.4.2 Pharmacophore Modeling 278
10.5 Conclusions and Recommendations 281
References 282
Part Three Applications and Practical Guidelines 291
11 Applied Virtual Screening: Strategies, Recommendations, and Caveats 293
Dagmar Stumpfe and Jürgen Bajorath
11.1 Introduction 293
11.2 What Is Virtual Screening? 293
11.3 Spectrum of Virtual Screening Approaches 294
11.4 Molecular Similarity as a Foundation and Caveat of Virtual Screening 295
11.5 Goals of Virtual Screening 296
11.6 Applicability Domain 297
11.7 Reference and Database Compounds 299
11.8 Biological Activity versus Compound Potency 300
11.9 Methodological Complexity and Compound Class Dependence 301
11.10 Search Strategies and Compound Selection 302
11.11 Virtual and High-Throughput Screening 304
11.12 Practical Applications: An Overview 306
11.13 LFA-1 Antagonist 307
11.14 Selectivity Searching 310
11.15 Concluding Remarks 314
References 315
12 Applications and Success Stories in Virtual Screening 319
Hans Matter and Christoph Sotriffer
12.1 Introduction 319
12.2 Practical Considerations 320
12.3 Successful Applications of Virtual Screening 321
12.3.1 Structure-Based Virtual Screening 322
12.3.2 Structure-Based Library Design 336
12.3.3 Ligand-Based Virtual Screening 338
12.4 Conclusion 347
References 348
Part Four Scenarios and Case Studies: Routes to Success 359
13 Scenarios and Case Studies: Examples for Ligand-Based Virtual Screening 361
Trevor Howe, Daniele Bemporad, and Gary Tresadern
13.1 Introduction 361
13.2 1D Ligand-Based Virtual Screening 362
13.3 2D Ligand-Based Virtual Screening 363
13.3.1 Examples from the Literature 363
13.3.2 Applications at J&JPRD Europe 366
13.4 3D Ligand-Based Virtual Screening 368
13.4.1 Methods 370
13.4.2 3DLBVS Examples 372
13.5 Summary 376
References 377
14 Virtual Screening on Homology Models 381
Róbert Kiss and György M. Keseru"
14.1 Introduction 381
14.2 Homology Models versus Crystal Structures: Comparative Evaluation of Screening Performance 382
14.2.1 Soluble Proteins 382
14.2.2 Membrane Proteins 392
14.3 Challenges of Homology Model-Based Virtual Screening 394
14.3.1 Level of Sequence Identity 395
14.3.2 Main-Chain Flexibility 396
14.3.3 Side-Chain Conformation: Induced Fit Effects of Ligands 396
14.3.4 Loop Modeling 397
14.4 Case Studies 399
14.4.1 Virtual Screening on the Homology Model of Histamine H4 Receptor 399
14.4.2 Virtual Screening on the Homology Model of Janus Kinase 2 402
References 404
15 Target-Based Virtual Screening on Small-Molecule Protein Binding Sites 411
Ralf Heinke, Urszula Uciechowska, Manfred Jung, and Wolfgang Sippl
15.1 Introduction 411
15.1.1 Pharmacophore-Based Methods 412
15.1.2 Ligand Docking 412
15.1.3 Virtual Screening 413
15.1.4 Binding Free Energy Calculations 414
15.2 Structure-Based VS for Histone Arginine Methyltransferase PRMT1 Inhibitors 414
15.2.1 Structure-Based VS of the NCI Diversity Set 415
15.2.2 Pharmacophore-Based VS 417
15.3 Identification of Nanomolar Histamine H3 Receptor Antagonists by Structure- and Pharmacophore-Based VS 422
15.3.1 Generation of Homology Model of the hH3R and hH3R Antagonist Complexes 423
15.3.2 Validation of the Homology Model by Docking Known Antagonists into the hH3R Binding Site 424
15.3.3 Pharmacophore-Based VS 425
15.3.4 Experimental Testing of the Identified Hits 429
15.3.5 Discussion of the Applied VS Strategies 429
15.4 Summary 431
References 432
16 Target-Based Virtual Screening to Address Protein–Protein Interfaces 435
Olivier Sperandio, Maria A. Miteva, and Bruno O. Villoutreix
16.1 Introduction 435
16.2 Some Recent PPIM Success Stories 437
16.3 Protein–Protein Interfaces 438
16.3.1 Interface Pockets, Flexibility, and Hot Spots 440
16.3.2 Databases and Tools to Analyze Interfaces 442
16.4 PPIMs. Chemical Space and ADME/Tox Properties 442
16.5 Drug Discovery, Chemical Biology, and In Silico Screening Methods: Overview and Suggestions for PPIM Search 447
16.6 Case Studies 450
16.6.1 PPI Stabilizers: Superoxide Dismutase Type 1 450
16.6.2 PPI Inhibitors: Lck 452
16.6.3 Allosteric Inhibitors: Antitrypsin Polymerization 455
16.7 Conclusions and Future Directions 457
References 458
17 Fragment-Based Approaches in Virtual Screening 467
Danzhi Huang and Amedeo Caflisch
17.1 Introduction 467
17.2 In Silico Fragment-Based Approaches 468
17.3 Our Approach to High-Throughput Fragment-Based Docking 470
17.3.1 Decomposition of Compounds into Fragments 471
17.3.2 Docking of Anchor Fragments 471
17.3.3 Flexible Docking of Library Compounds 472
17.3.4 LIECE Binding Energy Evaluation 472
17.3.5 Consensus Scoring 475
17.3.6 In Silico Screening Campaigns 475
17.3.7 West Nile Virus NS3 Protease (Flaviviral Infections) 475
17.3.8 EphB4 Tyrosine Kinase (Cancer) 477
17.4 Lessons Learned from Our Fragment-Based Docking 479
17.5 Challenges of Fragment-Based Approaches 481
References 482
Appendix A: Software Overview 491
Appendix B: Virtual Screening Application Studies 501
Index 511