Molecular Modeling: Basic Principles and Applications / Edition 3

Molecular Modeling: Basic Principles and Applications / Edition 3

by Hans-Dieter Holtje, Wolfgang Sippl, Didier Rognan, Gerd Folkers

ISBN-10: 3527315683

ISBN-13: 9783527315680

Pub. Date: 01/28/2008

Publisher: Wiley

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,


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.

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Table of Contents

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

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