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 protein-ligand interaction modeling and analysis for both novices and experts.
PREFACE 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 Ligand-Induced 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 MM-Based Methods QM-Based 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 Internal Coordinates Fast Docking to Multiple Receptor Conformations Single Receptor Conformation Multiple Receptor Conformations Improving Poor Homology Models of the Binding Pocket State of the Art: GPCR Dock 2010 Modeling and Docking Assessment Conclusions and Outlook PROSPECTS OF MODULATING PROTEIN?PROTEIN INTERACTIONS Introduction Thermodynamics of Protein?Protein Interactions CADD Methods for the Identification and Optimization of Small-Molecule Inhibitors of PPIs Examples of CADD Applied to PPIs Summary
Holger Gohlke is Professor of Pharmaceutical and Medicinal Chemistry at the Heinrich-Heine-University, Dusseldorf, Germany. He obtained his diploma in chemistry from the Technical University of Darmstadt and his PhD from Philipps-University, Marburg, working with Gerhard Klebe, where he developed the DrugScore and AFMoC approaches. He then did postdoctoral research at The Scripps Research Institute, La Jolla, USA, working with David Case on developing and evaluating computational biophysical methods to predict protein-protein interactions. After appointments as Assistant Professor at Goethe University Frankfurt and Professor at Christian-Albrechts-University, Kiel, he moved to Dusseldorf in 2009. He was awarded the 'Innovationspreis in Medizinischer und Pharmazeutischer Chemie' from the Gesellschaft Deutscher Chemiker and the Deutsche Pharmazeutische Gesellschaft, and the Hansch Award of the Cheminformatics and QSAR Society. His current research focuses on the understanding, prediction, and modulation of interactions involving biological macromolecules from a theoretical perspective. His group applies and develops techniques grounded in bioinformatics, computational biology, and computational biophysics.