Computational and Structural Approaches to Drug Discovery

by Stroud, Robert M.; Finer-Moore, Janet

• ISBN13: 9780854043651
• ISBN10: 0854043659
• Edition: 1st
• Format: Hardcover
• Copyright: 2007-11-19
• Publisher: Royal Society of Chemistry

Summary

Computational methods impact all aspects of modern drug discovery and most notably these methods move rapidly from academic exercises to becoming drugs in clinical trials... This insightful book represents the experience and understanding of the global experts in the field and spotlights both the structural and medicinal chemistry aspects of drug design. The need to 'encode' the factors that determine adsorption, distribution, metabolism, excretion and toxicology are explored, as they remain the critical issues in this area of research. This indispensable resource provides the reader with: * A rich understanding of modern approaches to docking * A comparison and critical evaluation of state-of-the-art methods * Details on harnessing computational methods for both analysis and prediction * An insight into prediction potencies and protocols for unbiased evaluations of docking and scoring algorithms * Critical reviews of current fragment based methods with perceptive applications to kinases Addressing a wide range of uses of protein structures for drug discovery the Editors have created and essential reference for professionals in the pharmaceutical industry and moreover an indispensable core text for all graduate level courses covering molecular interactions and drug discovery.

Table of Contents

Overview
Facing the Wall in Computationally Based Approaches to Drug Discovery
The Promise, and the Problem	p. 3
Current Limitations in Structure-guided Lead Design	p. 5
Lessons in Structure-based Drug Design from Thymidylate Synthase	p. 7
Mechanism-based Inhibitors and Enzyme-catalyzed Therapeutics	p. 7
Iterative Structure-based Drug Design	p. 8
Docking, Fragments and Optimizability	p. 8
New Developments in Structure-based Drug-design Methods	p. 13
Fragment-based Methods	p. 13
Identifying Drug Target Sites on a Protein	p. 16
Targeting Protein-Protein Interactions	p. 17
Computational Docking to Nominated Sites	p. 18
Conclusion	p. 19
References	p. 20
The Changing Landscape in Drug Discovery
Introduction	p. 24
QSAR - Understanding Without Prediction	p. 25
Gene Technology - from Mice to Humans	p. 27
Combinatorial Library Design - Driven by Medicinal Chemistry	p. 28
Docking and Scoring - Solved and Unsolved Problems	p. 32
Virtual Screening - the Road to Success	p. 35
Fragment-based and Combinatorial Design - A New Challenge	p. 37
Summary and Conclusions	p. 38
References	p. 41
Structure-Based Design
Purine Nucleoside Phosphorylase
Introduction	p. 49
Three-dimensional Structures of PNPs	p. 51
Related Enzymes of the PNP Family	p. 54
PNP Active Sites	p. 55
Human PNP Inhibitors	p. 58
Other Applications of Molecular Design to PNP	p. 62
Applications of Molecular Design to Enzymes Related to PNP	p. 64
PNP Inhibitors and Clinical Trials	p. 65
Conclusions and Future Directions	p. 66
Note Added in Proof	p. 66
References	p. 67
Application and Limitations of X-Ray Crystallographic Data in Structure-Guided Ligand and Drug Design
Introduction	p. 73
Structure-guided Ligand Design and Drug Design	p. 74
Some Limitations in the Use of X-ray Data	p. 79
Basic Crystallography Terms	p. 79
Uncertainty in the Identity or Location of Protein or Ligand Atoms	p. 83
Effect of Crystallization Conditions	p. 86
Identification and Location of Water	p. 87
Macromolecular Structures to Determine Small-molecule Structures	p. 88
Assessing the Validity of Structure Models	p. 89
Summary and Outlook	p. 90
References	p. 91
Dealing with Bound Waters in a Site: Do they Leave or Stay?
Introduction	p. 95
Localized Water Molecules in Binding Sites of Proteins	p. 96
Identifying Localized Water Molecules from Computer Simulations	p. 99
Calculation of Free-energy Cost of Displacing a Site-bound Water Molecule	p. 101
Inclusion of Explicit Water Molecules in Drug Discovery	p. 104
Acknowledgements	p. 106
References	p. 106
Knowledge-Based Methods in Structure-Based Design
Introduction	p. 111
Atom-based Potentials	p. 111
Group-based Potentials	p. 112
Methodologies	p. 114
The Reference State	p. 115
Volume Corrections	p. 116
Applications	p. 117
Visualization and Interaction 'Hot Spots'	p. 117
Docking and Scoring	p. 118
De Novo Design	p. 120
Targeted Scoring Functions	p. 120
Discussion	p. 121
Conclusion	p. 123
References	p. 123
Combating Drug Resistance - Identifying Resilient Molecular Targets and Robust Drugs
Introduction	p. 127
Resilient Targets and Robust Drugs	p. 128
Example of HIV-1 Protease: Substrate Recognition vs. Drug Resistance	p. 129
Implications for Future Structure-based Drug Design	p. 132
Acknowledgements	p. 132
References	p. 132
Docking
Docking Algorithms and Scoring Functions; State-of-the-Art and Current Limitations
Introduction	p. 137
Binding Mode Prediction	p. 138
Virtual Screening for Lead Identification	p. 139
Potency Prediction for Lead Optimization	p. 139
A Brief Review of Recent Docking Evaluations	p. 140
What these Evaluations Tell us about the Performance of Docking Algorithms	p. 143
Binding Mode Predictions	p. 143
Virtual Screening	p. 144
Affinity Prediction	p. 145
How an Ideal Evaluation Data Set Might be Structured	p. 147
Binding Mode Prediction	p. 147
Virtual Screening	p. 148
Affinity Prediction	p. 148
Concluding Remarks	p. 149
Binding Mode Prediction	p. 149
Virtual Screening	p. 150
Rank Order by Affinity	p. 151
The State-of-the-art	p. 152
References	p. 153
Application of Docking Methods to Structure-Based Drug Design
Introduction	p. 155
Docking Methods, Capabilities and Limitations	p. 156
Molecule Preparation	p. 156
Sampling Methods	p. 157
Scoring Methods	p. 160
Managing Errors in Docking	p. 162
How is Docking Applied to Drug Design?	p. 164
Drug Target Selection and Characterization	p. 165
Lead Compound Discovery	p. 168
Lead Compound Optimization	p. 171
Summary	p. 172
References	p. 172
Strength in Flexibility: Modeling Side-Chain Conformational Change in Docking and Screening
Introduction	p. 181
Background	p. 181
Improving Docking and Screening Through Side-chain Flexibility Modeling	p. 181
Enhancing Target Specificity Through Flexibility Modeling	p. 182
Approaches	p. 183
The State of the Art in Modeling Protein Side-chain Flexibility	p. 183
Learning from Nature: Observing Side-chain Motions Upon Ligand Binding	p. 185
The Future: Knowledge-based Modeling of Side-chain Motions	p. 189
Acknowledgements	p. 189
References	p. 190
Avoiding the Rigid Receptor: Side-Chain Rotamers
Introduction	p. 192
Rotamer Libraries	p. 194
Successful Applications of Rotamer Libraries in Drug Design	p. 195
Aspartic Acid Protease Inhibitors	p. 195
Matrix Metalloproteinase-1 Inhibitors	p. 195
Thymidylate Synthase Inhibitors	p. 199
Protein Tyrosine Phosphatase 1B Inhibitors	p. 200
HIV Protease Drug-resistant Mutants Bound to Inhibitors	p. 201
Trypsin-benzamidine and Phosphocholine-McPC 603	p. 201
11.4 Conclusions	p. 202
Acknowledgements	p. 202
References	p. 202
Screening
Computational Prediction of Aqueous Solubility, Oral Bioavailability, P450 Activity and hERG Channel Blockade
Introduction	p. 207
Aqueous Solubility	p. 208
Oral Bioavailability	p. 211
Cytochrome P450 Activity	p. 212
hERG Channel Blockade	p. 215
Conclusions	p. 219
References	p. 220
Shadows on Screens
Introduction	p. 223
Phenomenology of Aggregation	p. 224
What Sort of Compounds Aggregate?	p. 227
Mechanism of Aggregation-based Inhibition	p. 232
A Rapid Counter-screen for Aggregation-based Inhibitors	p. 233
Biological Implications?	p. 239
The Spirit-haunted World of Screening	p. 239
Acknowledgements	p. 240
References	p. 240
Iterative Docking Strategies for Virtual Ligand Screening
Introduction	p. 242
AutoDock Background	p. 243
Scoring Function	p. 243
Search Function	p. 244
AutoDockTools	p. 244
AutoDockTools Analysis	p. 245
Diversity-based Virtual Screening Studies	p. 246
AICAR Transformylase	p. 246
Protein Phosphatase 2C	p. 246
Comparison with Existing VLS Strategies	p. 253
Hierarchical VLS	p. 256
Monolithic VLS Strategy	p. 258
Other AutoDock VLS Studies	p. 259
Acetylcholine Esterase Peripheral Anionic Site	p. 259
Human P2Y[subscript 1] Receptor	p. 260
Diversity-based vs. Issues	p. 260
Library Choice	p. 260
Similarity Search	p. 261
Apo Versus Ligand-bound Docking Models	p. 262
Binding Site Choices	p. 263
Future Work	p. 264
References	p. 264
Challenges and Progresses in Calculations of Binding Free Energies - What Does it Take to Quantify Electrostatic Contributions to Protein-Ligand Interactions?
Introduction	p. 268
Computational Strategies	p. 269
Free-energy Perturbation, Linear Response Approximation and Potential of Mean Force Calculations by All-atom Models	p. 269
Proper and Improper Treatments of Long-range Effects in All-atom Models	p. 273
Calculations of Electrostatic Energies by Simplified Models	p. 274
Calculating Binding Free Energies	p. 277
Studies of Drug Mutations by FEP Approaches	p. 277
Evaluation of Absolute Binding Energies by the LRA and LIE Approaches	p. 278
Using Semi-macroscopic and Macroscopic Approaches in Studies of Ligand Binding	p. 279
Protein-protein Interactions	p. 281
Challenges and New Advances	p. 282
Perspectives	p. 285
Acknowledgement	p. 285
References	p. 285
Fragment-Based Design
Discovery and Extrapolation of Fragment Structures towards Drug Design
Structure-based Approaches to Drug Discovery	p. 293
Properties of Molecular Fragments	p. 294
From Molecular Fragments to Drug Leads	p. 296
Fragment Growing	p. 296
Fragment Linking	p. 297
Fragment Assembly	p. 299
Screening and Identification of Fragments	p. 300
X-ray Crystallography for Fragment-based Lead Identification	p. 301
NMR Spectroscopy	p. 302
Protein-based Methods: Structure-activity Relationship by NMR	p. 302
Ligand-based Methods	p. 303
Mass Spectrometry	p. 306
Covalent Mass Spectrometric Methods	p. 306
Non-covalent Mass Spectrometric Methods	p. 307
Looking at the Protein or the Ligand	p. 308
Thermal Shift	p. 309
Isothermal Titration Calorimetry	p. 309
Surface Plasmon Resonance	p. 310
Concluding Remarks	p. 311
Acknowledgements	p. 311
References	p. 311
A Link Means a Lot: Disulfide Tethering in Structure-Based Drug Design
Introduction: What is Disulfide Tethering?	p. 319
Success of Native Cysteine Tethering	p. 323
Role of Structure in Engineered-cysteine Tethering	p. 325
Cooperative Tethering	p. 328
Extended Tethering	p. 330
Breakaway Tethering	p. 333
Discovery of Novel Allosteric Sites with Tethering	p. 335
Tethering as a Validation Tool	p. 339
Tethering vs. Traditional Medicinal Chemistry	p. 340
Tethering in Structural Determination	p. 341
The Challenge of Covalency	p. 342
Hydrophobic Binders	p. 343
Conclusions: The Future of Tethering	p. 344
References	p. 345
The Impact of Protein Kinase Structures on Drug Discovery
Introduction	p. 349
The Hinge Region and the Concept of Kinase Inhibitor Scaffold	p. 351
High-throughput Crystallography for the Discovery of Novel Scaffolds	p. 353
High Potency-High Specificity-High Molecular (H3) Weight Screening	p. 353
Low Potency-Low Specificity-Low Molecular Weight (L3) Screening	p. 354
The Gatekeeper Residue and the Selectivity Pocket	p. 355
The Conformational States of the DFG Motif and the Opening of the Back Pocket	p. 357
Allosteric Inhibitors, Non-ATP Competitive Inhibitors, and Irreversible Inhibitors	p. 359
Discovering Kinase Inhibitors in a 500-Dimensional Space	p. 360
Acknowledgement	p. 361
References	p. 361
Subject Index	p. 366
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