Molecular Modeling Basic Principles and

Ideal for beginners, this book explains the basics of modeling in a competent yet easily understandable way. Following complete sections on the modeling of small molecules, protein modeling and chemogenomics, completely worked-out examples show the way to the reader's first modeling experiment.This new, third edition features a new chapter on chemogenomics, reflecting the trend towards 'chemical biology', as well as the protein modeling example being completely rewritten for a better 'feel' of modeling complex biomolecules.The authors are experienced university teachers who regularly hold courses on molecular modeling, making this a tried-and-tested text for teachers. It is equally valuable for experts, since it is the only book to evaluate the strengths and limitations of the molecular modeling techniques and software currently available.

Hans-Dieter H+¦ltje is director of the Institute of Pharmaceutical Chemistry at the Heinrich-Heine-Universit+ñt D++sseldorf (Germany) where he also holds the chair of Medicinal Chemistry. His main interest is the molecular mechanism of drug action.

Wolfgang Sippl is Professor of Pharmaceutical Chemistry at the Martin-Luther-University of Halle-Wittenberg (Germany). He is interested in 3D QSAR, molecular docking and molecular dynamics, and their applications in drug design and pharmacokinetics.

Didier Rognan leads the Drug Bioinformatics Group at the Laboratory for Molecular Pharmacochemistry in Illkirch (France). He is mainly interested in all aspects (method development, applications) of protein-based drug design and virtual screening.

Gerd Folkers is Professor of Pharmaceutical Chemistry at the ETH Z++rich (Switzerland). The focus of his research is the molecular interation between drugs and their binding sites.

Preface to the Third Edition	p. X
Introduction	p. 1
Modern History of Molecular Modeling	p. 2
Do Today's Molecular Modeling Methods Only Make Pictures of the Lukretian World or Do They Make Anything More?	p. 3
What are Models Used For?	p. 4
Molecular Modeling Uses all Four Kinds for Model Building	p. 5
The Final Step Is Design	p. 5
Scope of the Book	p. 6
Small Molecules	p. 9
Generation of 3D Coordinates	p. 9
Crystal Data	p. 9
Fragment Libraries	p. 10
Conversion of 2D Structural Data into 3D Form	p. 12
References	p. 15
Computational Tools for Geometry Optimization	p. 16
Force Fields	p. 16
Geometry Optimization	p. 19
Energy-minimizing Procedures	p. 21
Use of Charges, Solvation Effects	p. 23
Quantum Mechanical Methods	p. 24
References	p. 29
Conformational Analysis	p. 32
Conformational Analysis Using Systematic Search Procedures	p. 34
Conformational Analysis Using Monte Carlo Methods	p. 37
Conformational Analysis Using Molecular Dynamics	p. 39
Which Is the Method of Choice?	p. 44
References	p. 46
Determination of Molecular Interaction Potentials	p. 50
Molecular Electrostatic Potentials (MEPs)	p. 50
Molecular Interaction Fields	p. 57
Display of Properties on a Molecular Surface	p. 66
References	p. 66
Further Reading	p. 69
Pharmacophore Identification	p. 70
Molecules to be Matched	p. 70
Atom-by-atom Superposition	p. 72
Superposition of Molecular Fields	p. 74
References	p. 75
3D QSAR Methods	p. 77
The CoMFA Method	p. 77
Other CoMFA-related Methods	p. 81
More 3D QSAR Methods	p. 83
Receptor-based 3D QSAR	p. 84
Reliability of 3D QSAR Models	p. 86
References	p. 87
Further Reading	p. 91
A Case Study for Small Molecule Modeling: Dopamine D[subscript 3] Receptor Antagonists	p. 93
A Pharmacophore Model for Dopamine D[subscript 3] Receptor Antagonists	p. 93
The Aromatic-Basic Fragment	p. 99
The Spacer	p. 100
The Aromatic-Amidic Residue	p. 101
Resulting Pharmacophore	p. 102
Molecular Interaction Fields	p. 102
3D QSAR Analysis	p. 104
Variable Reduction and PLS Model	p. 104
Validation of the Model	p. 107
Prediction of External Ligands	p. 108
References	p. 110
Introduction to Comparative Protein Modeling	p. 111
Where and How to Get Information on Proteins	p. 111
References	p. 115
Terminology and Principles of Protein Structure	p. 116
Conformational Properties of Proteins	p. 116
Types of Secondary Structural Elements	p. 119
Homologous Proteins	p. 122
References	p. 124
Comparative Protein Modeling	p. 126
Procedures for Sequence Alignments	p. 127
Determination and Generation of Structurally Conserved Regions (SCRs)	p. 133
Construction of Structurally Variable Regions (SVRs)	p. 135
Side-Chain Modeling	p. 136
Distance Geometry Approach	p. 138
Secondary Structure Prediction	p. 139
Threading Methods	p. 141
References	p. 144
Optimization Procedures - Model Refinement - Molecular Dynamics	p. 149
Force Fields for Protein Modeling	p. 149
Geometry Optimization	p. 150
The Use of Molecular Dynamics Simulations in Model Refinement	p. 151
Treatment of Solvated Systems	p. 153
Ligand-binding Site Complexes	p. 155
References	p. 155
Validation of Protein Models	p. 158
Stereochemical Accuracy	p. 158
Packing Quality	p. 164
Folding Reliability	p. 166
References	p. 169
Properties of Proteins	p. 173
Electrostatic Potential	p. 173
Interaction Potentials	p. 177
Hydrophobicity	p. 177
References	p. 178
Virtual Screening and Docking	p. 181
Preparation of the Partners	p. 181
Preparation of the Compound Library	p. 181
Representation of Proteins and Ligands	p. 186
Docking Algorithms	p. 189
Incremental Construction Methods	p. 189
Genetic Algorithms	p. 191
Tabu Search	p. 192
Simulated Annealing and Monte Carlo Simulations	p. 194
Shape-fitting Methods	p. 195
Miscellaneous Approaches	p. 195
Scoring Functions	p. 196
Empirical Scoring Functions	p. 196
Force-field-based Scoring Functions	p. 198
Knowledge-based Scoring Functions	p. 198
Critical Overview of Fast Scoring Functions	p. 199
Postfiltering Virtual Screening Results	p. 200
Filtering by Topological Properties	p. 200
Filtering by Consensus Mining Approaches	p. 200
Filtering by Combining Computational Procedures	p. 201
Filtering by Chemical Diversity	p. 201
Filtering by Visual Inspection	p. 202
Comparison of Different Docking and Scoring Methods	p. 202
Examples of Successful Virtual Screening Studies	p. 203
Outlook	p. 206
References	p. 207
Scope and Limits of Molecular Docking	p. 217
Docking in the Polar Active Site that Contains Water Molecules	p. 218
Including Cofactor in Docking?	p. 225
Impact of Tautomerism on Docking	p. 227
References	p. 229
Further Reading	p. 231
Chemogenomic Approaches to Rational Drug Design	p. 233
Description of Ligand and Target Spaces	p. 235
Ligand Space	p. 236
Target Space	p. 238
Protein-Ligand Space	p. 240
Ligand-based Chemogenomic Approaches	p. 242
Annotating Ligand Libraries	p. 242
Privileged Structures	p. 244
Ligand-based In silico Screening	p. 246
Target-based Chemogenomic Approaches	p. 249
Sequence-based Comparisons	p. 249
Structure-based Comparisons	p. 251
Target-Ligand-based Chemogenomic Approaches	p. 254
Chemical Annotation of Target Binding Sites	p. 254
Two-dimensional Searches	p. 256
Three-dimensional Searches	p. 256
Concluding Remarks	p. 258
References	p. 258
A Case Study for Protein Modeling: the Nuclear Hormone Receptor CAR as an Example for Comparative Modeling and the Analysis of Protein-Ligand Complexes	p. 265
The Biochemical and Pharmacological Description of the Problem	p. 265
Nuclear Hormone Receptor Superfamily	p. 265
Molecular Architecture and Activation Mechanisms of Nuclear Hormone Receptors	p. 265
The Human Constitutive Active Androstan Receptor (CAR)	p. 267
CAR Ligands	p. 267
Comparative Modeling of the Human Nuclear Hormone Receptor CAR	p. 268
Choosing Appropriate Template Structures	p. 269
Homology Modeling of the Human CAR	p. 271
Setting up the System for the Molecular Dynamics Simulations	p. 271
Analysis of the Models that Emerged from MD Simulations	p. 272
Atomic Fluctuations	p. 272
AF-2 Interaction Domain	p. 275
Deciphering the Structural Basis for Constitutive Activity of Human CAR	p. 276
Coactivator Binding	p. 278
Analysis of CAR Mutants	p. 279
Identifying Important Amino Acids for CAR Activation	p. 279
MD Simulations of Selected CAR Mutants	p. 282
Modeling of CAR-Ligand Complexes	p. 284
The CAR X-ray Structure Comes into Play	p. 286
How Accurate is the Generated CAR Model?	p. 286
Docking Studies Using the CAR X-ray Structure	p. 288
The Basis for Constitutive Activity Revisited	p. 289
Virtual Screening for Novel CAR Activators	p. 292
Concluding Remarks	p. 295
References	p. 296
Index	p. 299
Table of Contents provided by Ingram. All Rights Reserved.

What is included with this book?

The New copy of this book will include any supplemental materials advertised. Please check the title of the book to determine if it should include any access cards, study guides, lab manuals, CDs, etc.

The Used, Rental and eBook copies of this book are not guaranteed to include any supplemental materials. Typically, only the book itself is included. This is true even if the title states it includes any access cards, study guides, lab manuals, CDs, etc.

FREE SHIPPING

Amazon no longer offers textbook rentals. We do!

Molecular Modeling Basic Principles and Applications

Summary

Author Biography

Table of Contents

Supplemental Materials