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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 | |