Protein-Ligand Interactions

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.

• PREFACE PART I: Binding Thermodynamics STATISTICAL THERMODYNAMICS OF BINDING AND MOLECULAR RECOGNITION MODELSIntroductory RemarksThe Binding Constant and Free EnergyA Statistical Mechanical Treatment of BindingStrategies for Calculating Binding Free Energies SOME PRACTICAL RULES FOR THE THERMODYNAMIC OPTIMIZATIONOF DRUG CANDIDATESEngineering Binding ContributionsEliminating Unfavorable EnthalpyImproving Binding EnthalpyImproving Binding AffinityImproving SelectivityThermodynamic Optimization Plot ENTHALPY?ENTROPY COMPENSATION AS DEDUCED FROM MEASUREMENTSOF TEMPERATURE DEPENDENCEIntroductionThe Current Status of Enthalpy?Entropy CompensationMeasurement of the Entropy and Enthalpy of ActivationAn ExampleThe Compensation TemperatureEffect of High Correlation on Estimates of Entropy and EnthalpyEvolutionary ConsiderationsTextbooks 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 OPTIMIZATIONBackgroundSPR Biosensor TechnologyFrom Interaction Models to Kinetic Rate Constants and AffinityAffinity versus Kinetic Rate Constants for Evaluation of InteractionsFrom Models to MechanismsStructural InformationThe Use of Kinetic Rate Constants in Lead Generation and OptimizationDesigning Compounds with Optimal PropertiesConclusions NMR METHODS FOR THE DETERMINATION OF PROTEIN?LIGAND INTERACTIONSExperimental Parameters from NMRAspects of Protein?Ligand Interactions That Can Be Addressed by NMRLigand-Induced Conformational Changes of a Cyclic Nucleotide Binding DomainLigand Binding to GABARAP Binding Site and Affinity MappingTransient Binding of Peptide Ligands to Membrane Proteins PART III: Modeling Protein?Ligand Interactions POLARIZABLE FORCE FIELDS FOR SCORING PROTEIN?LIGAND INTERACTIONSIntroduction and OverviewAMOEBA Polarizable Potential Energy ModelAMOEBA Explicit Water Simulation ApplicationsImplicit Solvent Calculation Using AMOEBA Polarizable Force FieldConclusions and Future Directions QUANTUM MECHANICS IN STRUCTURE-BASED LIGAND DESIGNIntroductionThree MM-Based MethodsQM-Based Force FieldsQM Calculations of Ligand Binding SitesQM/MM CalculationsQM Calculations of Entire ProteinsConcluding Remarks HYDROPHOBIC ASSOCIATION AND VOLUME-CONFINED WATER MOLECULESIntroductionWater as a Whole in Hydrophobic AssociationConfined Water Molecules in Protein?Ligand Binding IMPLICIT SOLVENT MODELS AND ELECTROSTATICS IN MOLECULAR RECOGNITIONIntroductionPoisson?Boltzmann MethodsThe Generalized Born ModelReference Interaction Site Model of Molecular SolvationApplications LIGAND AND RECEPTOR CONFORMATIONAL ENERGIESThe Treatment of Ligand and Receptor Conformational Energy in Various Theoretical Formulations of BindingComputational Results on Ligand Conformational EnergyComputational Results on Receptor Conformational EnergyConcluding Remarks FREE ENERGY CALCULATIONS IN DRUG LEAD OPTIMIZATIONModern Drug DesignFree Energy CalculationsExample Protocols and ApplicationsDiscussion SCORING FUNCTIONS FOR PROTEIN?LIGAND INTERACTIONSIntroductionScoring 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 PREDICTIONIntroductionDruggability: Ligand PropertiesDruggability: Ligand BindingDruggability Prediction by Protein ClassDruggability Predictions: Experimental MethodsDruggability Predictions: Computational MethodsA Test Case: PTP1BOutlook and Concluding Remarks EMBRACING PROTEIN PLASTICITY IN LIGAND DOCKINGIntroductionDocking by Sampling Internal CoordinatesFast Docking to Multiple Receptor ConformationsSingle Receptor ConformationMultiple Receptor ConformationsImproving Poor Homology Models of the Binding PocketState of the Art: GPCR Dock 2010 Modeling and Docking AssessmentConclusions and Outlook PROSPECTS OF MODULATING PROTEIN?PROTEIN INTERACTIONSIntroductionThermodynamics of Protein?Protein InteractionsCADD Methods for the Identification and Optimization of Small-Molecule Inhibitors of PPIsExamples of CADD Applied to PPIsSummary