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Computational and Structural Approaches to Drug Discovery : Ligand-Protein Interactions - Robert Stroud

Computational and Structural Approaches to Drug Discovery

Ligand-Protein Interactions

By: Robert Stroud (Editor), Janet Finer-Moore (Editor)

Hardcover Published: 26th October 2007
ISBN: 9780854043651
Number Of Pages: 382

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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 an 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.

Industry Reviews

The book has been carefully constructed as a series of essays, each addressing an important topic, and even better, topics, that there are many misunderstandings and misconceptions about.Each chapter is well referenced and serves as a good entry point into the literature.I would also strongly recommend this book to medicinal chemists leading project teams that use structural information. * Chemistry World, March 2008, 77 (Richard Lewis) *

Overview
Facing the Wall in Computationally Based Approaches to Drug Discovery
The Promise, and the Problemp. 3
Current Limitations in Structure-guided Lead Designp. 5
Lessons in Structure-based Drug Design from Thymidylate Synthasep. 7
Mechanism-based Inhibitors and Enzyme-catalyzed Therapeuticsp. 7
Iterative Structure-based Drug Designp. 8
Docking, Fragments and Optimizabilityp. 8
New Developments in Structure-based Drug-design Methodsp. 13
Fragment-based Methodsp. 13
Identifying Drug Target Sites on a Proteinp. 16
Targeting Protein-Protein Interactionsp. 17
Computational Docking to Nominated Sitesp. 18
Conclusionp. 19
Referencesp. 20
The Changing Landscape in Drug Discovery
Introductionp. 24
QSAR - Understanding Without Predictionp. 25
Gene Technology - from Mice to Humansp. 27
Combinatorial Library Design - Driven by Medicinal Chemistryp. 28
Docking and Scoring - Solved and Unsolved Problemsp. 32
Virtual Screening - the Road to Successp. 35
Fragment-based and Combinatorial Design - A New Challengep. 37
Summary and Conclusionsp. 38
Referencesp. 41
Structure-Based Design
Purine Nucleoside Phosphorylase
Introductionp. 49
Three-dimensional Structures of PNPsp. 51
Related Enzymes of the PNP Familyp. 54
PNP Active Sitesp. 55
Human PNP Inhibitorsp. 58
Other Applications of Molecular Design to PNPp. 62
Applications of Molecular Design to Enzymes Related to PNPp. 64
PNP Inhibitors and Clinical Trialsp. 65
Conclusions and Future Directionsp. 66
Note Added in Proofp. 66
Referencesp. 67
Application and Limitations of X-Ray Crystallographic Data in Structure-Guided Ligand and Drug Design
Introductionp. 73
Structure-guided Ligand Design and Drug Designp. 74
Some Limitations in the Use of X-ray Datap. 79
Basic Crystallography Termsp. 79
Uncertainty in the Identity or Location of Protein or Ligand Atomsp. 83
Effect of Crystallization Conditionsp. 86
Identification and Location of Waterp. 87
Macromolecular Structures to Determine Small-molecule Structuresp. 88
Assessing the Validity of Structure Modelsp. 89
Summary and Outlookp. 90
Referencesp. 91
Dealing with Bound Waters in a Site: Do they Leave or Stay?
Introductionp. 95
Localized Water Molecules in Binding Sites of Proteinsp. 96
Identifying Localized Water Molecules from Computer Simulationsp. 99
Calculation of Free-energy Cost of Displacing a Site-bound Water Moleculep. 101
Inclusion of Explicit Water Molecules in Drug Discoveryp. 104
Acknowledgementsp. 106
Referencesp. 106
Knowledge-Based Methods in Structure-Based Design
Introductionp. 111
Atom-based Potentialsp. 111
Group-based Potentialsp. 112
Methodologiesp. 114
The Reference Statep. 115
Volume Correctionsp. 116
Applicationsp. 117
Visualization and Interaction 'Hot Spots'p. 117
Docking and Scoringp. 118
De Novo Designp. 120
Targeted Scoring Functionsp. 120
Discussionp. 121
Conclusionp. 123
Referencesp. 123
Combating Drug Resistance - Identifying Resilient Molecular Targets and Robust Drugs
Introductionp. 127
Resilient Targets and Robust Drugsp. 128
Example of HIV-1 Protease: Substrate Recognition vs. Drug Resistancep. 129
Implications for Future Structure-based Drug Designp. 132
Acknowledgementsp. 132
Referencesp. 132
Docking
Docking Algorithms and Scoring Functions; State-of-the-Art and Current Limitations
Introductionp. 137
Binding Mode Predictionp. 138
Virtual Screening for Lead Identificationp. 139
Potency Prediction for Lead Optimizationp. 139
A Brief Review of Recent Docking Evaluationsp. 140
What these Evaluations Tell us about the Performance of Docking Algorithmsp. 143
Binding Mode Predictionsp. 143
Virtual Screeningp. 144
Affinity Predictionp. 145
How an Ideal Evaluation Data Set Might be Structuredp. 147
Binding Mode Predictionp. 147
Virtual Screeningp. 148
Affinity Predictionp. 148
Concluding Remarksp. 149
Binding Mode Predictionp. 149
Virtual Screeningp. 150
Rank Order by Affinityp. 151
The State-of-the-artp. 152
Referencesp. 153
Application of Docking Methods to Structure-Based Drug Design
Introductionp. 155
Docking Methods, Capabilities and Limitationsp. 156
Molecule Preparationp. 156
Sampling Methodsp. 157
Scoring Methodsp. 160
Managing Errors in Dockingp. 162
How is Docking Applied to Drug Design?p. 164
Drug Target Selection and Characterizationp. 165
Lead Compound Discoveryp. 168
Lead Compound Optimizationp. 171
Summaryp. 172
Referencesp. 172
Strength in Flexibility: Modeling Side-Chain Conformational Change in Docking and Screening
Introductionp. 181
Backgroundp. 181
Improving Docking and Screening Through Side-chain Flexibility Modelingp. 181
Enhancing Target Specificity Through Flexibility Modelingp. 182
Approachesp. 183
The State of the Art in Modeling Protein Side-chain Flexibilityp. 183
Learning from Nature: Observing Side-chain Motions Upon Ligand Bindingp. 185
The Future: Knowledge-based Modeling of Side-chain Motionsp. 189
Acknowledgementsp. 189
Referencesp. 190
Avoiding the Rigid Receptor: Side-Chain Rotamers
Introductionp. 192
Rotamer Librariesp. 194
Successful Applications of Rotamer Libraries in Drug Designp. 195
Aspartic Acid Protease Inhibitorsp. 195
Matrix Metalloproteinase-1 Inhibitorsp. 195
Thymidylate Synthase Inhibitorsp. 199
Protein Tyrosine Phosphatase 1B Inhibitorsp. 200
HIV Protease Drug-resistant Mutants Bound to Inhibitorsp. 201
Trypsin-benzamidine and Phosphocholine-McPC 603p. 201
11.4 Conclusionsp. 202
Acknowledgementsp. 202
Referencesp. 202
Screening
Computational Prediction of Aqueous Solubility, Oral Bioavailability, P450 Activity and hERG Channel Blockade
Introductionp. 207
Aqueous Solubilityp. 208
Oral Bioavailabilityp. 211
Cytochrome P450 Activityp. 212
hERG Channel Blockadep. 215
Conclusionsp. 219
Referencesp. 220
Shadows on Screens
Introductionp. 223
Phenomenology of Aggregationp. 224
What Sort of Compounds Aggregate?p. 227
Mechanism of Aggregation-based Inhibitionp. 232
A Rapid Counter-screen for Aggregation-based Inhibitorsp. 233
Biological Implications?p. 239
The Spirit-haunted World of Screeningp. 239
Acknowledgementsp. 240
Referencesp. 240
Iterative Docking Strategies for Virtual Ligand Screening
Introductionp. 242
AutoDock Backgroundp. 243
Scoring Functionp. 243
Search Functionp. 244
AutoDockToolsp. 244
AutoDockTools Analysisp. 245
Diversity-based Virtual Screening Studiesp. 246
AICAR Transformylasep. 246
Protein Phosphatase 2Cp. 246
Comparison with Existing VLS Strategiesp. 253
Hierarchical VLSp. 256
Monolithic VLS Strategyp. 258
Other AutoDock VLS Studiesp. 259
Acetylcholine Esterase Peripheral Anionic Sitep. 259
Human P2Y[subscript 1] Receptorp. 260
Diversity-based vs. Issuesp. 260
Library Choicep. 260
Similarity Searchp. 261
Apo Versus Ligand-bound Docking Modelsp. 262
Binding Site Choicesp. 263
Future Workp. 264
Referencesp. 264
Challenges and Progresses in Calculations of Binding Free Energies - What Does it Take to Quantify Electrostatic Contributions to Protein-Ligand Interactions?
Introductionp. 268
Computational Strategiesp. 269
Free-energy Perturbation, Linear Response Approximation and Potential of Mean Force Calculations by All-atom Modelsp. 269
Proper and Improper Treatments of Long-range Effects in All-atom Modelsp. 273
Calculations of Electrostatic Energies by Simplified Modelsp. 274
Calculating Binding Free Energiesp. 277
Studies of Drug Mutations by FEP Approachesp. 277
Evaluation of Absolute Binding Energies by the LRA and LIE Approachesp. 278
Using Semi-macroscopic and Macroscopic Approaches in Studies of Ligand Bindingp. 279
Protein-protein Interactionsp. 281
Challenges and New Advancesp. 282
Perspectivesp. 285
Acknowledgementp. 285
Referencesp. 285
Fragment-Based Design
Discovery and Extrapolation of Fragment Structures towards Drug Design
Structure-based Approaches to Drug Discoveryp. 293
Properties of Molecular Fragmentsp. 294
From Molecular Fragments to Drug Leadsp. 296
Fragment Growingp. 296
Fragment Linkingp. 297
Fragment Assemblyp. 299
Screening and Identification of Fragmentsp. 300
X-ray Crystallography for Fragment-based Lead Identificationp. 301
NMR Spectroscopyp. 302
Protein-based Methods: Structure-activity Relationship by NMRp. 302
Ligand-based Methodsp. 303
Mass Spectrometryp. 306
Covalent Mass Spectrometric Methodsp. 306
Non-covalent Mass Spectrometric Methodsp. 307
Looking at the Protein or the Ligandp. 308
Thermal Shiftp. 309
Isothermal Titration Calorimetryp. 309
Surface Plasmon Resonancep. 310
Concluding Remarksp. 311
Acknowledgementsp. 311
Referencesp. 311
A Link Means a Lot: Disulfide Tethering in Structure-Based Drug Design
Introduction: What is Disulfide Tethering?p. 319
Success of Native Cysteine Tetheringp. 323
Role of Structure in Engineered-cysteine Tetheringp. 325
Cooperative Tetheringp. 328
Extended Tetheringp. 330
Breakaway Tetheringp. 333
Discovery of Novel Allosteric Sites with Tetheringp. 335
Tethering as a Validation Toolp. 339
Tethering vs. Traditional Medicinal Chemistryp. 340
Tethering in Structural Determinationp. 341
The Challenge of Covalencyp. 342
Hydrophobic Bindersp. 343
Conclusions: The Future of Tetheringp. 344
Referencesp. 345
The Impact of Protein Kinase Structures on Drug Discovery
Introductionp. 349
The Hinge Region and the Concept of Kinase Inhibitor Scaffoldp. 351
High-throughput Crystallography for the Discovery of Novel Scaffoldsp. 353
High Potency-High Specificity-High Molecular (H3) Weight Screeningp. 353
Low Potency-Low Specificity-Low Molecular Weight (L3) Screeningp. 354
The Gatekeeper Residue and the Selectivity Pocketp. 355
The Conformational States of the DFG Motif and the Opening of the Back Pocketp. 357
Allosteric Inhibitors, Non-ATP Competitive Inhibitors, and Irreversible Inhibitorsp. 359
Discovering Kinase Inhibitors in a 500-Dimensional Spacep. 360
Acknowledgementp. 361
Referencesp. 361
Subject Indexp. 366
Table of Contents provided by Ingram. All Rights Reserved.

ISBN: 9780854043651
ISBN-10: 0854043659
Series: RSC Biomolecular Sciences (unnumbered)
Audience: Professional
Format: Hardcover
Language: English
Number Of Pages: 382
Published: 26th October 2007
Country of Publication: GB
Dimensions (cm): 24.08 x 16.41  x 2.69
Weight (kg): 0.76

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