Catalogue


Physico-chemical and computational approaches to drug discovery /
edited by F. Javier Luque and Xavier Barril.
imprint
Cambridge, U.K. : Royal Society of Chemistry, c2012.
description
xxiii, 418 p. : ill. (some col.) ; 24 cm.
ISBN
1849733538 (hbk.), 9781849733533 (hbk.)
format(s)
Book
Holdings
More Details
imprint
Cambridge, U.K. : Royal Society of Chemistry, c2012.
isbn
1849733538 (hbk.)
9781849733533 (hbk.)
abstract
This title covers a wide range of topics relevant to the development of drugs. It provides a comprehensive description of the major methodological strategies available for rational drug discovery.
catalogue key
8758325
 
Includes bibliographical references and index.
A Look Inside
Summaries
Back Cover Copy
This book provides an updated description of the advances experienced in recent years in the field of molecular modeling and simulation of biomolecular recognition, with particular emphasis towards the development of efficient strategies in structure-based drug design. It is aimed towards both academic and industrial researchers working in modeling of biomolecular systems and drug discovery.The main aims of the book are to provide a detailed description of the physico-chemical principles that underlie the ligand-receptor interaction, to describe the methodological basis of computational tools to elucidate the molecular features that modulate the ligand-receptor interaction and to highlight the impact of the methodological innovations in drug design.The publication covers a wide range of topics relevant to the development of drugs and provides, in a single volume, a comprehensive description of the major methodological strategies available for drug discovery. There are two main features that make this book unique: firstly, the contents provide a physical basis of the methodological tools described in the book, which capture the essential physico-chemical properties inherent to the recognition between ligands and their receptors. This provides the reader with clear guidelines to calibrate the performance of the current methodologies used in drug design. Secondly, the combination of standard formalisms widely accepted in the pharmaceutical and medicinal chemistry arena are included, with an updated review of the latest advances experienced in the field.
Back Cover Copy
This book provides an updated review of the latest advances experienced in recent years in the field of molecular modelling and simulation of biomolecular recognition, with particular emphasis towards the development of efficient strategies in structure-based drug design. The main aims of the book are to provide a detailed description of the physico-chemical principles that underlie the ligand-receptor interaction, to describe the methodological basis of computational tools to elucidate the molecular features that modulate the ligand-receptor interaction and to highlight the impact of the methodological innovations in drug design. The publication covers a wide range of topics relevant to the development of drugs and provides, in a single volume, a comprehensive description of the major methodological strategies available for rational drug discovery. There are two main features that make this book unique. Firstly, the contents are oriented to provide a physico-chemical basis of the methodological tools described in the book, which capture the essential features inherent to the recognition between ligands and their receptors. Secondly, standard formalisms widely accepted in the pharmaceutical and medicinal chemistry arena are presented with an updated review of the latest advances experienced in the field. Overall, the contents of the book provide the reader with clear guidelines to calibrate the performance of the current methodologies used in drug design. The book will be essential reading for academic and industrial researchers working in modelling of biomolecular systems and drug discovery.
Back Cover Copy
This book provides an updated review of the latest advances experienced in recent years in the field of molecular modelling and simulation of biomolecular recognition, with particular emphasis towards the development of efficient strategies in structure-based drug design. The main aims of the book are to provide a detailed description of the physico-chemical principles that underlie the ligand-receptor interaction, to describe the methodological basis of computational tools to elucidate the molecular features that modulate the ligand-receptor interaction and to highlight the impact of the methodological innovations in drug design.The publication covers a wide range of topics relevant to the development of drugs and provides, in a single volume, a comprehensive description of the major methodological strategies available for rational drug discovery. There are two main features that make this book unique. Firstly, the contents are oriented to provide a physico-chemical basis of the methodological tools described in the book, which capture the essential features inherent to the recognition between ligands and their receptors. Secondly, standard formalisms widely accepted in the pharmaceutical and medicinal chemistry arena are presented with an updated review of the latest advances experienced in the field. Overall, the contents of the book provide the reader with clear guidelines to calibrate the performance of the current methodologies used in drug design.The book will be essential reading for academic and industrial researchers working in modelling of biomolecular systems and drug discovery.
Bowker Data Service Summary
This title covers a wide range of topics relevant to the development of drugs. It provides a comprehensive description of the major methodological strategies available for rational drug discovery.
Description for Bookstore
The book covers a wide range of topics relevant to the development of drugs. Though this might prevent an in-depth analysis of very specific issues relevant in the pharmaceutical arena, it has the advantage of providing in a single volume a rather comprehensive description of the major methodological strategies available for rational drug discovery. There are two main features that distinguish this book from previous titles in the field. First, the contents are oriented to provide a physico-chemical basis of the methodological tools described in the book, which should capture the essential features inherent to the recognition between ligands and their receptors. This will provide the reader with clear guidelines to calibrate the performance of the current methodologies used in drug design. Second, the combination of standard formalisms widely accepted in the pharmaceutical and medicinal chemistry arena with an updated review of the latests advances experienced in the field.
Description for Bookstore
This book provides an updated description of the advances experienced in recent years in the field of molecular modeling and simulation of biomolecular recognition, with particular emphasis towards the development of efficient strategies in structure-based drug design. It is aimed towards both academic and industrial researchers working in modeling of biomolecular systems and drug discovery.The main aims of the book are to provide a detailed description of the physico-chemical principles that underlie the ligand-receptor interaction, describe the methodological basis of computational tools to elucidate the molecular features that modulate the ligand-receptor interaction and highlight the impact of the methodological innovations in drug design.
Main Description
Molecular modeling and simulation play a central role in academic and industrial research focused on physico-chemical properties and processes. The efforts carried out in this field have crystallized in a variety of models, simulation methods, and computational techniques that are examining the relationship between the structure, dynamics and functional role of biomolecules and their interactions. In particular, there has been a huge advance in the understanding of the molecular determinants that mediate the interaction between small compounds acting as ligands and their macromolecular targets. This book provides an updated description of the advances experienced in recent years in the field of molecular modeling and simulation of biomolecular recognition, with particular emphasis towards the development of efficient strategies in structure-based drug design.
Main Description
Molecular modeling and simulation play a central role in academic and industrial research focused on physico-chemical properties and processes. The efforts carried out in this field have crystallized in a variety of models, simulation methods, and computational techniques that are examining the relationship between the structure, dynamics and functional role of biomolecules and their interactions. In particular, there has been a huge advance in the understanding of the molecular determinants that mediate the interaction between small compounds acting as ligands and their macromolecular targets. This book provides an updated description of the advances experienced in recent years in the field of molecular modeling and simulation of biomolecular recognition, with particular emphasis towards the development of efficient strategies in structure-based drug design. The main aims of the book are:* To provide a detailed description of the physico-chemical principles that underlie the ligand-receptor interaction* To describe the methodological basis of computational tools to elucidate the molecular features that modulate the ligand-receptor interaction* To highlight the impact of the methodological innovations in drug designThe publication covers a wide range of topics relevant to the development of drugs and provides, in a single volume, a comprehensive description of the major methodological strategies available for drug discovery. There are two main features that make this book unique: firstly, the contents provide a physical basis of the methodological tools described in the book, which capture the essential physico-chemical properties inherent to the recognition between ligands and their receptors. This provides the reader with clear guidelines to calibrate the performance of the current methodologies used in drug design. Secondly, the combination of standard formalisms widely accepted in the pharmaceutical and medicinal chemistry arena are included, with an updated review of the latest advances experienced in the field. This current state-of-the-art publication covers the current challenges faced by computational tools to decipher the basis of ligand-receptor interaction and is aimed towards both academic and industrial researchers working in modeling of biomolecular systems and drug discovery.
Main Description
This book provides an updated review of the latest advances experienced in recent years in the field of molecular modelling and simulation of biomolecular recognition, with particular emphasis towards the development of efficient strategies in structure-based drug design. The main aims of the book are to provide a detailed description of the physico-chemical principles that underlie the ligand-receptor interaction, to describe the methodological basis of computational tools to elucidate the molecular features that modulate the ligand-receptor interaction and to highlight the impact of the methodological innovations in drug design. The publication covers a wide range of topics relevant to the development of drugs and provides, in a single volume, a comprehensive description of the major methodological strategies available for rational drug discovery. There are two main features that make this book unique. Firstly, the contents are oriented to provide a physico-chemical basis of the methodological tools described in the book, which capture the essential features inherent to the recognition between ligands and their receptors. Secondly, standard formalisms widely accepted in the pharmaceutical and medicinal chemistry arena are presented with an updated review of the latest advances experienced in the field. Overall, the contents of the book provide the reader with clear guidelines to calibrate the performance of the current methodologies used in drug design. The book will be essential reading for academic and industrial researchers working in modelling of biomolecular systems and drug discovery. Book jacket.
Table of Contents
Recognition of Ligands by Macromolecular Targetsp. 1
Physical Basis of Ligand-Protein Bindingp. 1
Prediction of Binding Affinities: Free Energy Calculationsp. 4
Quantum Mechanical-Guided Refinements in Interaction Energy Potentialsp. 7
Quantum Mechanical Methods in Ligand-Protein Interactionsp. 11
Summary and Outlookp. 17
Acknowledgementsp. 18
Referencesp. 18
Thermodynamics of Ligand Bindingp. 23
Introductionp. 23
Theoretical Backgroundp. 24
Basic Equations of Ligand-Protein Binding Thermodynamicsp. 24
Details of the Ligand-Receptor Binding Process; the Role of the Solventp. 24
Ligand Properties and Binding Thermodynamicsp. 28
Measuring Binding Thermodynamicsp. 35
Isothermal Titration Calorimetryp. 35
Van't Hoff Analysisp. 37
Further Notes on Experimental Approachesp. 38
Calculation of the Binding Free Energy and Its Componentsp. 38
Molecular Simulation-Based Computational Methodsp. 38
Other Computational Methodsp. 42
Summary of Binding Free Energy Calculationsp. 46
Impact of Thermodynamics on Medicinal Chemistry Optimizationsp. 47
Property Shifts and Medicinal Chemistry Optimizationsp. 47
Optimization Strategiesp. 51
Thermodynamics-Guided Medicinal Chemistry Optimizationp. 52
Case Studiesp. 56
Renin Inhibitorsp. 56
Carbonic Anhydrase Inhibitorsp. 58
Matrix Metalloproteinase (MMP12) Inhibitorsp. 60
Heat Shock Protein (HSP90) Inhibitorsp. 62
Adenosine A1 Receptor Ligandsp. 64
Trypsin Inhibitorsp. 66
Thrombin Inhibitorsp. 68
Adenosine A2A Antagonistsp. 70
Summaryp. 72
Acknowledgementsp. 73
Referencesp. 73
Continuum Solvation in Biomolecular Systemsp. 80
Solvation Models in Binding Affinity Prediction and Scoring Functionsp. 80
Continuum Solvation Modelsp. 83
Continuum Electrostaticsp. 83
Nonpolar Contributionp. 86
Capturing Discrete Water in Continuum Solvation Modelsp. 88
Semi-Explicit Assembly (SEA) Continuum Modelp. 90
First Shell of Hydration (FiSH) Continuum Modelp. 93
Analytical Generalized Born plus Nonpolar Implicit Solvent Model 2 (AGBNP2)p. 95
Three-Dimensional Reference Interaction Site Model (3D-RISM)p. 96
Other Recent Models Capturing First-Shell Effectsp. 97
Concluding Remarksp. 97
Referencesp. 98
Bioavailability Prediction at Early Drug Discovery Stages: In Vitro Assays and Simple Physico-Chemical Rulesp. 104
Bioavailabilityp. 104
Internal Dataset Used in This Chapterp. 106
Permeabilityp. 107
Permeability In Vitro Assaysp. 108
Permeability: Simple Rulesp. 111
Solubilityp. 115
Solubility In Vitro Assaysp. 116
Solubility: Simple Rulesp. 118
First-Pass Metabolismp. 120
Intrinsic Clearance In Vitro Assaysp. 121
Intrinsic Clearance: Simple Rulesp. 122
The Whole Picture: Putting the Pieces Togetherp. 123
Referencesp. 126
Molecular Descriptors for Database Mining. Translating Empirical Chemistry into Mathematics: Tools for QSAR and In Silico Screening Based on the Hydrophobicity of Small Moleculesp. 128
Introductionp. 128
The History of QSARp. 130
The Evolving Dimensionality of QSAR Methodsp. 131
Descriptors and Molecular Propertiesp. 133
Electronic Descriptorsp. 133
Steric Descriptorsp. 134
Hydrophobic Descriptorsp. 135
Connectivity and Related Descriptorsp. 136
Information Encoded in Empirical Hydrophobic Descriptorsp. 136
Nano-Scale Icebergs and Entropyp. 138
Hydrophobic Fieldsp. 138
Additional Free Energy Informationp. 139
Absorption, Distribution, Metabolism and Excretion (ADME)p. 139
Estimation of log Pp. 140
HINT: an Empirical log P-Based Paradigm for Drug Discoveryp. 141
Treating Hydrophobicity as a 3D Propertyp. 143
The HINT 3D Mapsp. 143
Virtual Screening and Modeling with an Empirical Force Fieldp. 145
Referencesp. 145
Pharmacophore Models in Drug Designp. 151
Introductionp. 151
Ligand-Based Pharmacophore Elucidationp. 153
Feature Representationp. 153
Alignmentp. 155
Scoring Functionsp. 157
Recent Methodsp. 158
Evaluation of Pharmacophore Methodsp. 158
Datasets for Ligand-Based Pharmacophore Elucidationp. 159
Validation of Pharmacophore Hypothesesp. 159
Application of Pharmacophores in Virtual Screeningp. 159
Receptor-Based Pharmacophoresp. 161
Pharmacophores and 3D QSARp. 163
Example Applications of Pharmacophoresp. 164
Ligand-Based Pharmacophoresp. 164
Receptor-Based Pharmacophoresp. 166
Conclusionsp. 167
Referencesp. 167
Docking and Virtual Screeningp. 171
Introductionp. 171
Molecular Docking Methodsp. 172
Search Methodsp. 173
Target Validation and Preparationp. 176
Target Flexibilityp. 180
Ligand Selection and Preparationp. 180
Evaluating Docking Resultsp. 182
Virtual Screeningp. 184
Conclusionp. 187
Acknowledgementsp. 188
Referencesp. 188
Binding Free Energy Calculation and Scoring in Small-Molecule Dockingp. 195
Introductionp. 195
Binding Free Energyp. 197
Physico-Chemical Aspects of Protein-Ligand Bindingp. 197
Binding Free Energy Calculationp. 198
Scoring Functions in High-Throughput Dockingp. 199
General Considerationsp. 199
Scoring Functionsp. 200
Comparison of Scoring Functionsp. 203
Limitations of Scoring Functions: Can They Be Improved?p. 204
Post-Docking Processing in High-Throughput Dockingp. 207
Rescoring of Top-Ranking Hits Using Advanced Simulation Techniquesp. 208
Conclusionsp. 214
Referencesp. 215
Accounting for Target Flexibility During Ligand-Receptor Dockingp. 223
Introductionp. 223
Thermodynamic Driving Forces of Binding and the Scoring Problemp. 225
Molecular Motions of Proteins and Ligandsp. 227
Accounting for Conformational Flexibility During Dockingp. 228
Inclusion of Ligand Flexibilityp. 228
Accounting Implicitly for Receptor Flexibilityp. 228
Ligand-Receptor Docking Using Molecular Dynamics Simulationsp. 229
Treatment of Side-Chain Flexibility and Local Protein Backbone Changesp. 231
Conformational Ensemble Methodsp. 232
Employing Structural Ensembles in Docking Calculationsp. 233
Use of Collective Modes to Describe Global Motionsp. 235
Conclusions and Outlookp. 238
Acknowledgementsp. 239
Referencesp. 239
COMparative BINding Energy (COMBINE) Analysis as a Structure-Based 3D-QSAR Methodp. 244
Introductionp. 244
COMparative BINding Energy (COMBINE) Analysisp. 246
A Historical Perspectivep. 246
The Statistics Behind COMBINEp. 249
gCOMBINE: the Graphical User Interface to COMBINEp. 253
3D-QSAR Models in Virtual Screeningp. 254
Retrospective Studiesp. 255
Prospective Studiesp. 256
3-D QSAR Pharmacophoresp. 257
3D-QSAR Modeling of Ligand Selectivityp. 258
Current Trends in COMBINE Analysis as a 3D-QSAR Techniquep. 260
COMBINE Analysis as a Scoring Function for Virtual Screeningp. 261
COMBINE Analysis for Modeling Target Flexibility and/or Ligand Orientationp. 262
COMBINE Analysis for Modeling Ligand Selectivityp. 263
SemiEmpirical COMBINE (SE-COMBINE) Analysisp. 265
Future Challenges for COMBINE Analysisp. 266
Conclusionsp. 267
Acknowledgementsp. 268
Referencesp. 268
Enhanced Sampling Methods in Drug Designp. 273
Introductionp. 273
Basicsp. 276
Fixed Energy Systems (NVE)p. 276
Fixed Temperature Systems (NVT)p. 278
Isothermal-Isobaric Systems (NPT)p. 279
Microscopic Estimators of Thermodynamic Observablesp. 279
Numerical Integration of the Equations of Motion in Molecular Dynamicsp. 280
Description of the Binding Processp. 283
Identification of Sub-States in a Given Thermodynamic Ensemblep. 283
The Role of Free Energy and the Concept of Reaction Coordinatep. 283
Volumetric Effect on the Unbound Statep. 285
Basics of Enhanced Samplingp. 286
The Importance of Sampling and the "Importance Sampling"p. 286
Collective Variablesp. 287
Enhanced Sampling Techniquesp. 287
Enhanced Sampling Applications to Protein-Ligand Bindingp. 291
Steered Molecular Dynamicsp. 292
Metadynamicsp. 294
Conclusions and Perspectivesp. 296
Referencesp. 298
Expanding the Target Space: Druggability Assessmentsp. 302
Introductionp. 302
The Target Spacep. 303
Privileged Target Classesp. 303
Under-Exploited Molecular Mechanism of Actionp. 305
Properties of Drug Binding Sitesp. 305
Druggability: Term Definition and Controversyp. 306
Experimental Determination of Druggabilityp. 307
High-Throughout Screeningp. 307
Fragment Screeningp. 308
Multiple Solvent Crystal Structuresp. 308
Computational Assessment of Druggabilityp. 309
Data Setsp. 309
Cavity Detection Algorithmsp. 310
Methods Based on Cavity Descriptorsp. 311
Methods Based on Interaction Potentialsp. 313
Summary and Outlookp. 315
Acknowledgementsp. 315
Referencesp. 315
Computational Strategies and Challenges for Targeting Protein-Protein Interactions with Small Moleculesp. 319
Introductionp. 319
What Makes Protein-Protein Interfaces Difficult to Target?p. 320
Computational Hot Spot Detectionp. 324
Predicting Potential Binding Sites in Protein-Protein Interfaces from Unbound Protein Statesp. 328
Allosteric Binding Sites as Alternative Targets for Modulating Protein-Protein Interactionsp. 331
Docking for Targeting Protein-Protein Interfacesp. 334
Improved Descriptions of Solvent Effectsp. 334
Protein Flexibility in Protein-Ligand Dockingp. 337
Data-Driven Docking Approachesp. 342
Summary and Outlookp. 346
Acknowledgementsp. 348
Referencesp. 348
Using Molecular Simulations and Metadynamics to Predict Binding Free Energies and Kinetics: the Case of Cox and Cdk2p. 360
Introductionp. 360
Methodsp. 361
Metadynamicsp. 361
The Choice of the CVsp. 362
Path Collective Variablesp. 362
Optimal Collective Variables for Ligand Bindingp. 364
Results and Discussionp. 365
Binding Profiles for a Series of CDK2 Inhibitorsp. 365
Rationalizing the Different Residence Times of a Ligand in COX Isoformsp. 367
Conclusionsp. 368
Referencesp. 369
Computer-Assisted Design of Drug-Like Synthetic Librariesp. 372
Introductionp. 372
Methods and Formats in Computer-Assisted Library Designp. 374
Examples of Computer-Assisted Library Designp. 376
Viral Diseasesp. 376
Parasitic Diseasesp. 388
Bacterial Diseasesp. 389
Conclusionsp. 394
Acknowledgementsp. 394
Referencesp. 394
Subject Indexp. 399
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