Innovative and forward-looking, this volume focuses on recent achievements in this rapidly progressing field and looks at future potential for development. The first part provides a basic understanding of the factors governing protein-ligand interactions, followed by a comparison of key experimental methods (calorimetry, surface plasmon resonance, NMR) used in generating interaction data. The second half of the book is devoted to insilico methods of modeling and predicting molecular recognition and binding, ranging from first principles-based to approximate ones. Here, as elsewhere in the book, emphasis is placed on novel approaches and recent improvements to established methods. The final part looks at unresolved challenges, and the strategies to address them. With the content relevant for all drug classes and therapeutic fields, this is an inspiring and often-consulted guide to the complexity of proteinligand interaction modeling and analysis for both novices and experts.

InhaltsangabePREFACE PART I: Binding Thermodynamics STATISTICAL THERMODYNAMICS OF BINDING AND MOLECULAR RECOGNITION MODELS Introductory Remarks The Binding Constant and Free Energy A Statistical Mechanical Treatment of Binding Strategies for Calculating Binding Free Energies SOME PRACTICAL RULES FOR THE THERMODYNAMIC OPTIMIZATION OF DRUG CANDIDATES Engineering Binding Contributions Eliminating Unfavorable Enthalpy Improving Binding Enthalpy Improving Binding Affinity Improving Selectivity Thermodynamic Optimization Plot ENTHALPY?ENTROPY COMPENSATION AS DEDUCED FROM MEASUREMENTS OF TEMPERATURE DEPENDENCE Introduction The Current Status of Enthalpy?Entropy Compensation Measurement of the Entropy and Enthalpy of Activation An Example The Compensation Temperature Effect of High Correlation on Estimates of Entropy and Enthalpy Evolutionary Considerations Textbooks PART II: Learning from Biophysical Experiments INTERACTION KINETIC DATA GENERATED BY SURFACE PLASMON RESONANCE BIOSENSORS AND THE USE OF KINETIC RATE CONSTANTS IN LEAD GENERATION AND OPTIMIZATION Background SPR Biosensor Technology From Interaction Models to Kinetic Rate Constants and Affinity Affinity versus Kinetic Rate Constants for Evaluation of Interactions From Models to Mechanisms Structural Information The Use of Kinetic Rate Constants in Lead Generation and Optimization Designing Compounds with Optimal Properties Conclusions NMR METHODS FOR THE DETERMINATION OF PROTEIN?LIGAND INTERACTIONS Experimental Parameters from NMR Aspects of Protein?Ligand Interactions That Can Be Addressed by NMR LigandInduced Conformational Changes of a Cyclic Nucleotide Binding Domain Ligand Binding to GABARAP Binding Site and Affinity Mapping Transient Binding of Peptide Ligands to Membrane Proteins PART III: Modeling Protein?Ligand Interactions POLARIZABLE FORCE FIELDS FOR SCORING PROTEIN?LIGAND INTERACTIONS Introduction and Overview AMOEBA Polarizable Potential Energy Model AMOEBA Explicit Water Simulation Applications Implicit Solvent Calculation Using AMOEBA Polarizable Force Field Conclusions and Future Directions QUANTUM MECHANICS IN STRUCTURE-BASED LIGAND DESIGN Introduction Three MMBased Methods QMBased Force Fields QM Calculations of Ligand Binding Sites QM/MM Calculations QM Calculations of Entire Proteins Concluding Remarks HYDROPHOBIC ASSOCIATION AND VOLUME-CONFINED WATER MOLECULES Introduction Water as a Whole in Hydrophobic Association Confined Water Molecules in Protein?Ligand Binding IMPLICIT SOLVENT MODELS AND ELECTROSTATICS IN MOLECULAR RECOGNITION Introduction Poisson?Boltzmann Methods The Generalized Born Model Reference Interaction Site Model of Molecular Solvation Applications LIGAND AND RECEPTOR CONFORMATIONAL ENERGIES The Treatment of Ligand and Receptor Conformational Energy in Various Theoretical Formulations of Binding Computational Results on Ligand Conformational Energy Computational Results on Receptor Conformational Energy Concluding Remarks FREE ENERGY CALCULATIONS IN DRUG LEAD OPTIMIZATION Modern Drug Design Free Energy Calculations Example Protocols and Applications Discussion SCORING FUNCTIONS FOR PROTEIN?LIGAND INTERACTIONS Introduction Scoring Protein?Ligand Interactions: What for and How to? Application of Scoring Functions: What Is Possible and What Is Not? Thermodynamic Contributions and Intermolecular Interactions: Which Are Accounted for and Which Are Not? Conclusions or What Remains to be Done and What Can be Expected? PART IV: Challenges in Molecular Recognition DRUGGABILITY PREDICTION Introduction Druggability: Ligand Properties Druggability: Ligand Binding Druggability Prediction by Protein Class Druggability Predictions: Experimental Methods Druggability Predictions: Computational Methods A Test Case: PTP1B Outlook and Concluding Remarks EMBRACING PROTEIN PLASTICITY IN LIGAND DOCKING Introduction Docking by Sampling Inte

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