Gohlke Protein-Ligand Interactions

1. Auflage 2012
ISBN: 978-3-527-64597-8
Verlag: Wiley-VCH
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 339 Seiten, E-Book

Reihe: Methods & Principles in Medicinal Chemistry

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.

Autoren/Hrsg.

Gohlke, Holger

Weitere Mitwirkende

Mannhold, Raimund

Kubinyi, Hugo

Folkers, Gerd

Inhaltsverzeichnis

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 C

Über Autor(innen)

Holger Gohlke is Professor of Pharmaceutical and Medicinal Chemistry at the Heinrich-Heine-University, Düsseldorf, 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 Düsseldorf 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.