Log In
Or create an account ->
Imperial Library
Home
About
News
Upload
Forum
Help
Login/SignUp
Index
Cover
Series
Title Page
Copyright
List of Contributors
Preface
A Personal Foreword
Section I
Chapter 1: The Binding Thermodynamics of Drug Candidates
1.1 Affinity Optimization
1.2 The Binding Affinity
1.3 The Enthalpy Change
1.4 The Entropy Change
1.5 Engineering Binding Contributions
1.6 Lipophilic Efficiency and Binding Enthalpy
Acknowledgments
References
Chapter 2: van't Hoff Based Thermodynamics
2.1 Relevance of Thermodynamics to Pharmacology
2.2 Affinity Constant Determination
2.3 The Origin of van't Hoff Equation
2.4 From van't Hoff toward Thermodynamic Discrimination
2.5 Representation of ΔG°, ΔH°, and ΔS° Data
2.6 The Adenosine Receptors Binding Thermodynamics Story
2.7 Binding Thermodynamics of G-Protein Coupled Receptors
2.8 Binding Thermodynamics of Ligand-Gated Ion Channel Receptors
2.9 Discussion
Abbreviations
References
Chapter 3: Computation of Drug-Binding Thermodynamics
3.1 Introduction
3.2 Potential of Mean Force Calculations
3.3 Alchemical Transformations
3.4 Nonequilibrium Methods
3.5 MM-PBSA
3.6 Linear Interaction Energy
3.7 Scoring Functions
3.8 Free-energy Components
3.9 Summary
References
Chapter 4: Thermodynamics-Guided Optimizations in Medicinal Chemistry
4.1 Introduction
4.2 The Thermodynamics of Medicinal Chemistry Optimizations
4.3 Selection of Suitable Starting Points
4.4 Thermodynamics Based Optimization Strategies
References
Chapter 5: From Molecular Understanding to Structure–Thermodynamic Relationships, the Case of Acetylcholine Binding Proteins
5.1 Introduction
5.2 Acetylcholine Binding Proteins (AChBPs)
5.3 Thermodynamics of Small Molecule Binding at AChBPs
5.4 Concluding Remarks and Outlook
References
Chapter 6: Thermodynamics in Lead Optimization
6.1 Introduction to Lead Optimization in Drug Discovery
6.2 Measurement of Thermodynamic Parameters in Lead Optimization
6.3 Advantages during Lead Optimization for Thermodynamic Measurements
6.4 Exploitation of Measured Thermodynamics in Lead Optimization
6.5 Lead Optimization beyond Affinity
6.6 Exemplary Case Studies
6.7 Potential Complicating Factors in Exploiting Thermodynamics in Lead Optimization
6.8 Summary
References
Chapter 7: Thermodynamic Profiling of Carbonic Anhydrase Inhibitors
7.1 Introduction
7.2 Thermodynamic Profiles of Fragment Inhibitors
7.3 Thermodynamics of Fragment Growing
7.4 Conclusions
Acknowledgments
References
Section II
Chapter 8: Drug–Target Residence Time
8.1 Introduction
8.2 Open and Closed Systems in Biology
8.3 Mechanisms of Drug–Target Interactions
8.4 Impact of Residence Time on Cellular Activity
8.5 Impact on Efficacy and Duration In vivo
8.6 Limitations of Drug–Target Residence Time
8.7 Summary
References
Chapter 9: Experimental Methods to Determine Binding Kinetics
9.1 Introduction
9.2 Definitions
9.3 Experimental Strategy
9.4 Experimental Methodologies
9.5 Specific Issues
9.6 Conclusion
Acknowledgment
References
Chapter 10: Challenges in the Medicinal Chemical Optimizationof Binding Kinetics
10.1 Introduction
10.2 Challenges
10.3 Optimization in Practice
10.4 Summary and Conclusions
References
Chapter 11: Computational Approaches for Studying Drug Binding Kinetics
11.1 Introduction
11.2 Theoretical Background
11.3 Model Types and Force Fields
11.4 Application Examples
11.5 Summary and Future Directions
Acknowledgments
References
Chapter 12: The Use of Structural Information to Understand Binding Kinetics
12.1 Introduction
12.2 Binding Kinetics
12.3 Methods to Obtain Structural Information to Understand Binding Kinetics
12.4 Literature on Structure Kinetic Relationships
12.5 Current Thinking on the Structural Factors That Influence Binding Kinetics
12.6 Concluding Remarks
References
Chapter 13: Importance of Drug–Target Residence Time at G Protein-Coupled Receptors – a Case for the Adenosine Receptors
13.1 Introduction
13.2 The Adenosine Receptors
13.3 Mathematical Definitions of Drug–Target Residence Time
13.4 Current Kinetic Radioligand Assays
13.5 Dual-Point Competition Association Assay: a Fast and High-Throughput Kinetic Screening Method
13.6 Drug–Target Residence Time: an Often Overlooked Key Aspect for a Drug's Mechanism of Action
13.7 Conclusions
Acknowledgments
References
Chapter 14: Case Study: Angiotensin Receptor Blockers (ARBs)
14.1 Introduction
14.2 Insurmountable Antagonism
14.3 From Partial Insurmountability to an Induced Fit-Binding Mechanism
14.4 Sartan Rebinding Contributes to Long-Lasting AT1-Receptor Blockade
14.5 Summary and Final Considerations
References
Chapter 15: The Kinetics and Thermodynamics of Staphylococcus aureus FabI Inhibition
15.1 Introduction
15.2 Fatty Acid Biosynthesis as a Novel Antibacterial Target
15.3 Inhibition of saFabI
15.4 Computer-Aided Enzyme Kinetics to Characterize saFabI Inhibition
15.5 Orthogonal Methods to Measure Drug–Target Residence Time
15.6 Mechanism-Dependent Slow-Binding Kinetics
15.7 Mechanistic Basis for Binary Complex Selectivity
15.8 Rational Design of Long Residence Time Inhibition
15.9 Summary
References
Section III
Chapter 16: Thermodynamics and Binding Kinetics in Drug Discovery
16.1 Introduction
16.2 Reaction Coordinate
16.3 Competing Rates
16.4 Thermodynamic Controlled Process – Competing Rates under Equilibrium Conditions
16.5 Kinetics Controlled Processes – Competing Rates under Non-equilibrium Conditions
16.6 Conformational Controlled Process – Kinetics as a Diagnostic for Conformational Change
16.7 The Value of Thermodynamics Measurements to Drug Discovery
16.8 Complementarity of Binding Kinetics and Thermodynamic to Discover Safer Medicines
References
Index
End User License Agreement
← Prev
Back
Next →
← Prev
Back
Next →