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| Preface to the Third Edition | |
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| Introduction | |
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| Modern History of Molecular Modeling | |
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| Do Today's Molecular Modeling Methods Only Make Pictures of the Lukretian World or Do They Make Anything More? | |
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| What are Models Used For? | |
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| Molecular Modeling Uses all Four Kinds for Model Building | |
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| The Final Step Is Design | |
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| Scope of the Book | |
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| Small Molecules | |
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| Generation of 3D Coordinates | |
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| Crystal Data | |
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| Fragment Libraries | |
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| Conversion of 2D Structural Data into 3D Form | |
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| References | |
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| Computational Tools for Geometry Optimization | |
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| Force Fields | |
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| Geometry Optimization | |
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| Energy-minimizing Procedures | |
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| Use of Charges, Solvation Effects | |
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| Quantum Mechanical Methods | |
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| References | |
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| Conformational Analysis | |
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| Conformational Analysis Using Systematic Search Procedures | |
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| Conformational Analysis Using Monte Carlo Methods | |
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| Conformational Analysis Using Molecular Dynamics | |
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| Which Is the Method of Choice? | |
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| References | |
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| Determination of Molecular Interaction Potentials | |
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| Molecular Electrostatic Potentials (MEPs) | |
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| Molecular Interaction Fields | |
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| Display of Properties on a Molecular Surface | |
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| References | |
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| Further Reading | |
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| Pharmacophore Identification | |
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| Molecules to be Matched | |
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| Atom-by-atom Superposition | |
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| Superposition of Molecular Fields | |
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| References | |
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| 3D QSAR Methods | |
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| The CoMFA Method | |
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| Other CoMFA-related Methods | |
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| More 3D QSAR Methods | |
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| Receptor-based 3D QSAR | |
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| Reliability of 3D QSAR Models | |
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| References | |
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| Further Reading | |
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| A Case Study for Small Molecule Modeling: Dopamine D[subscript 3] Receptor Antagonists | |
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| A Pharmacophore Model for Dopamine D[subscript 3] Receptor Antagonists | |
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| The Aromatic-Basic Fragment | |
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| The Spacer | |
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| The Aromatic-Amidic Residue | |
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| Resulting Pharmacophore | |
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| Molecular Interaction Fields | |
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| 3D QSAR Analysis | |
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| Variable Reduction and PLS Model | |
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| Validation of the Model | |
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| Prediction of External Ligands | |
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| References | |
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| Introduction to Comparative Protein Modeling | |
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| Where and How to Get Information on Proteins | |
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| References | |
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| Terminology and Principles of Protein Structure | |
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| Conformational Properties of Proteins | |
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| Types of Secondary Structural Elements | |
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| Homologous Proteins | |
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| References | |
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| Comparative Protein Modeling | |
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| Procedures for Sequence Alignments | |
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| Determination and Generation of Structurally Conserved Regions (SCRs) | |
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| Construction of Structurally Variable Regions (SVRs) | |
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| Side-Chain Modeling | |
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| Distance Geometry Approach | |
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| Secondary Structure Prediction | |
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| Threading Methods | |
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| References | |
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| Optimization Procedures - Model Refinement - Molecular Dynamics | |
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| Force Fields for Protein Modeling | |
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| Geometry Optimization | |
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| The Use of Molecular Dynamics Simulations in Model Refinement | |
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| Treatment of Solvated Systems | |
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| Ligand-binding Site Complexes | |
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| References | |
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| Validation of Protein Models | |
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| Stereochemical Accuracy | |
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| Packing Quality | |
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| Folding Reliability | |
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| References | |
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| Properties of Proteins | |
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| Electrostatic Potential | |
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| Interaction Potentials | |
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| Hydrophobicity | |
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| References | |
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| Virtual Screening and Docking | |
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| Preparation of the Partners | |
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| Preparation of the Compound Library | |
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| Representation of Proteins and Ligands | |
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| Docking Algorithms | |
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| Incremental Construction Methods | |
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| Genetic Algorithms | |
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| Tabu Search | |
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| Simulated Annealing and Monte Carlo Simulations | |
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| Shape-fitting Methods | |
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| Miscellaneous Approaches | |
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| Scoring Functions | |
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| Empirical Scoring Functions | |
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| Force-field-based Scoring Functions | |
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| Knowledge-based Scoring Functions | |
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| Critical Overview of Fast Scoring Functions | |
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| Postfiltering Virtual Screening Results | |
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| Filtering by Topological Properties | |
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| Filtering by Consensus Mining Approaches | |
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| Filtering by Combining Computational Procedures | |
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| Filtering by Chemical Diversity | |
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| Filtering by Visual Inspection | |
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| Comparison of Different Docking and Scoring Methods | |
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| Examples of Successful Virtual Screening Studies | |
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| Outlook | |
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| References | |
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| Scope and Limits of Molecular Docking | |
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| Docking in the Polar Active Site that Contains Water Molecules | |
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| Including Cofactor in Docking? | |
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| Impact of Tautomerism on Docking | |
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| References | |
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| Further Reading | |
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| Chemogenomic Approaches to Rational Drug Design | |
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| Description of Ligand and Target Spaces | |
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| Ligand Space | |
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| Target Space | |
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| Protein-Ligand Space | |
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| Ligand-based Chemogenomic Approaches | |
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| Annotating Ligand Libraries | |
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| Privileged Structures | |
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| Ligand-based In silico Screening | |
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| Target-based Chemogenomic Approaches | |
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| Sequence-based Comparisons | |
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| Structure-based Comparisons | |
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| Target-Ligand-based Chemogenomic Approaches | |
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| Chemical Annotation of Target Binding Sites | |
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| Two-dimensional Searches | |
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| Three-dimensional Searches | |
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| Concluding Remarks | |
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| References | |
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| A Case Study for Protein Modeling: the Nuclear Hormone Receptor CAR as an Example for Comparative Modeling and the Analysis of Protein-Ligand Complexes | |
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| The Biochemical and Pharmacological Description of the Problem | |
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| Nuclear Hormone Receptor Superfamily | |
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| Molecular Architecture and Activation Mechanisms of Nuclear Hormone Receptors | |
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| The Human Constitutive Active Androstan Receptor (CAR) | |
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| CAR Ligands | |
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| Comparative Modeling of the Human Nuclear Hormone Receptor CAR | |
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| Choosing Appropriate Template Structures | |
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| Homology Modeling of the Human CAR | |
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| Setting up the System for the Molecular Dynamics Simulations | |
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| Analysis of the Models that Emerged from MD Simulations | |
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| Atomic Fluctuations | |
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| AF-2 Interaction Domain | |
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| Deciphering the Structural Basis for Constitutive Activity of Human CAR | |
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| Coactivator Binding | |
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| Analysis of CAR Mutants | |
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| Identifying Important Amino Acids for CAR Activation | |
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| MD Simulations of Selected CAR Mutants | |
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| Modeling of CAR-Ligand Complexes | |
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| The CAR X-ray Structure Comes into Play | |
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| How Accurate is the Generated CAR Model? | |
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| Docking Studies Using the CAR X-ray Structure | |
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| The Basis for Constitutive Activity Revisited | |
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| Virtual Screening for Novel CAR Activators | |
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| Concluding Remarks | |
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| References | |
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| Index | |