Protein-Ligand Interactions: From Molecular Recognition to Drug Design

Cover Page......Page 1
Title Page......Page 4
ISBN 3527305211......Page 5
1 Prediction of Non-bonded Interactions in Drug Design......Page 6
4 The Biophore Concept......Page 7
5 Receptor-Ligand Interaction......Page 8
7 Principles of Enzyme-Inhibitor Design......Page 9
Subject Index......Page 10
Preface......Page 11
A Personal Foreword......Page 12
List of Contributors......Page 14
List of Abbreviations......Page 16
Prologue......Page 20
Introduction......Page 22
Major Contributions to Protein-Ligand Interactions......Page 23
Description of Scoring Functions for Receptor-Ligand Interactions......Page 27
Empirical Scoring Functions......Page 28
Knowledge-based Methods......Page 30
Influence of the Training Data......Page 31
Water Structure and Protonation State......Page 32
Successful Identification of Novel Leads Through Virtual Screening......Page 33
Outlook......Page 35
References......Page 36
Introduction and Scope......Page 40
Additivity of Pairwise Interactions – The Chelate Effect......Page 41
Geometric Fitting: The Hole-size Concept......Page 45
Di- and Polytopic Interactions: Change of Binding Mechanism with Different Fit......Page 47
Solvent Effects......Page 49
Enthalpy/Entropy Variations......Page 50
Conformational Pre-organization: Flexible vs. Rigid Hosts......Page 51
Selectivity and Stability in Supramolecular Complexes......Page 53
Induced Fit, Cooperativity, and Allosteric Effects......Page 55
Ion Pairs and Electrostatic Donor-Acceptor Interactions......Page 57
Hydrogen Bonds......Page 58
Weak Hydrogen Bonds: The Use of Intramolecular “Balances”......Page 61
Dispersive Interactions......Page 62
References......Page 65
Basic Thermodynamics of Protein-Ligand Interactions......Page 70
Measurement of Thermodynamic Parameters......Page 73
Calorimetric Determination of Thermodynamic Parameters......Page 74
van’t Hoff Determination of Thermodynamic Parameters......Page 76
Calorimetric Determination of Thermodynamic Parameters......Page 79
van’t Hoff Determination of Thermodynamic Parameters......Page 82
Caveats......Page 86
Summary......Page 87
References......Page 88
Introduction......Page 92
Methodology for Pharmacophore Detection and Searching......Page 93
Definition of Pharmacophoric Groups......Page 94
Ligand-based Methods for Pharmacophore Perception......Page 97
Protein Structure-based Pharmacophore Perception......Page 103
Methods for Pharmacophore Searching......Page 105
Pharmacophore Fingerprints......Page 107
Lead Generation......Page 110
Multi-pharmacophore Descriptors in Diversity Analysis and Library Design......Page 111
Structure-based Design......Page 114
The Biophore Concept in ADME Prediction......Page 117
Summary......Page 118
References......Page 119
The G-Protein-Coupled Receptors......Page 126
Ligand-binding Theory......Page 127
Receptor Material......Page 130
Binding Kinetics......Page 131
Radioligand-binding Assay......Page 134
Fluorescence Correlation Spectroscopy (FCS)......Page 135
Fluorescence Resonance Energy Transfer (FRET)......Page 136
Surface Plasmon Resonance......Page 137
Antibodies......Page 139
Applications of Antibodies......Page 141
Receptor Mutation and Ligand Modification......Page 144
Cross-linking......Page 149
Conclusion......Page 151
References......Page 152
The Importance of Hydrogen Bonds......Page 156
Defining the Hydrogen Bond......Page 157
Crystallographic Studies of Hydrogen Bonds......Page 158
The Geometry of Hydrogen Bonds......Page 159
NMR Studies of Hydrogen Bonds......Page 164
Thermodynamics of Hydrogen Bonding......Page 166
Experimental Thermodynamics of Biomolecular Hydrogen Bonds......Page 167
Bulk and Surface Water Molecules......Page 169
Buried Water Molecules......Page 170
Diverse Effects of Hydrogen Bonding on Drug Properties......Page 172
Optimizing Inhibitor Affinity......Page 173
Computational Tools for Hydrogen Bond Analysis and Design......Page 175
References......Page 177
Introduction......Page 182
The Heuristic Approach......Page 184
Mechanism-based Covalent Inhibitors......Page 185
Parallel de novo Design of Inhibitors......Page 187
Evolution of Inhibitors......Page 188
Inhibitors from Progressive Design......Page 189
Lessons from Classical Inhibitors......Page 191
Estimating the Energies of Interactions......Page 195
Water and Solvent......Page 197
Displacing a Tightly Bound Water......Page 198
Binding of Solvent Molecules......Page 199
Structure-Activity Relationships (SAR)......Page 200
Present Clinical Status of Thrombin Inhibitors......Page 201
Acknowledgments......Page 202
References......Page 203
Introduction......Page 206
Lipocalins: A Class of Natural Compound Carriers......Page 210
Anticalins: Lipocalins Reshaped via Combinatorial Biotechnology......Page 213
Structural Aspects of Ligand Recognition by Engineered Lipocalins......Page 218
Prospects and Future Applications of Anticalins......Page 224
References......Page 229
Introduction......Page 232
Conceptual Ideas......Page 233
Choice of Screening Fragments......Page 236
Experimental Approaches......Page 237
Background......Page 241
On-array Synthesis......Page 242
Off-array Synthesis and Spotting......Page 243
Detection Technology......Page 248
Protein Affinity Fingerprints......Page 250
Conclusion......Page 251
References......Page 253
B......Page 256
E......Page 257
I......Page 258
P......Page 259
S......Page 260
W......Page 261
Back Page......Page 262