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Informationen zum Autor Donald Huddler, Widener University Delaware Law School, Wilmington, USA. Edward R. Zartler is Chief Scientific Officer at Quantum Tessera Consulting, LLC, USA. Klappentext Applied Biophysics for Drug Discovery is a guide to new techniques and approaches to identifying and characterizing small molecules in early drug discovery. Biophysical methods are reasserting their utility in drug discovery and through a combination of the rise of fragment-based drug discovery and an increased focus on more nuanced characterisation of small molecule binding, these methods are playing an increasing role in discovery campaigns.This text emphasizes practical considerations for selecting and deploying core biophysical method, including but not limited to ITC, SPR, and both ligand-detected and protein-detected NMR.Topics covered include:* Design considerations in biophysical-based lead screening* Thermodynamic characterization of protein-compound interactions* Characterizing targets and screening reagents with HDX-MS* Microscale thermophoresis methods (MST)* Screening with Weak Affinity Chromatography* Methods to assess compound residence time* 1D-NMR methods for hit identification* Protein-based NMR methods for SAR development* Industry case studies integrating multiple biophysical methodsThis text is ideal for academic investigators and industry scientists planning hit characterization campaigns or designing and optimizing screening strategies. Zusammenfassung Applied Biophysics for Drug Discovery is a guide to new techniques and approaches to identifying and characterizing small molecules in early drug discovery. Inhaltsverzeichnis List of Contributors xiii 1 Introduction 1 Donald Huddler References 3 2 Thermodynamics in Drug Discovery 7 Ronan O'Brien, Natalia Markova, and Geoffrey A. Holdgate 2.1 Introduction 7 2.2 Methods for Measuring Thermodynamics of Biomolecular Interactions 8 2.2.1 Direct Method: Isothermal Titration Calorimetry 8 2.2.2 Indirect Methods: van't Hoff Analysis 8 2.2.2.1 Enthalpy Measurement Using van't Hoff Analysis 8 2.3 Thermodynamic?riven Lead Optimization 9 2.3.1 The Thermodynamic Rules of Thumb 9 2.3.2 Enthalpy-Entropy Compensation 10 2.3.3 Enthalpy-Entropy Transduction 13 2.3.4 The Role of Water 14 2.4 Enthalpy as a Probe for Binding 15 2.4.1 Thermodynamics in Fragment?ased Drug Design (FBDD) 15 2.4.2 Experimental Considerations and Limitations When Working with Fragments 16 2.4.3 Enthalpic Screening 17 2.5 Enthalpy as a Tool for Studying Complex Interactions 17 2.5.1 Identifying and Handling Complexity 17 2.6 Current and Future Prospects for Thermodynamics in Decision?aking Processes 24 References 25 3 Tailoring Hit Identification and Qualification Methods for Targeting Protein-Protein Interactions 29 Bj?n Walse, Andrew P. Turnbull, and Susan M. Boyd 3.1 Introduction 29 3.2 Structural Characteristics of PPI Interfaces 29 3.3 Screening Library Properties 31 3.3.1 Standard/Targeted Libraries/DOS 31 3.3.2 Fragment Libraries 33 3.3.3 Macrocyclic and Constrained Peptides 33 3.3.4 DNA?ncoded Libraries 34 3.4 Hit?inding Strategies 34 3.4.1 Small?olecule Approaches 36 3.4.2 Peptide?ased Approaches 38 3.4.3 In Silico Approaches 39 3.5 Druggability Assessment 39 3.5.1 Small Molecule: Ligand?ased Approaches 41 3.5.2 Small Molecule: Protein Structure?ased Approaches 41 3.6 Allosteric Inhibition of PPIs 42 3.7 Stabilization of PPIs 43 3.8 Case Studies 43 3.8.1 Primary Peptide Epitopes 43 3.8.1.1 Bromodomains 44 3.8.2 Secondary Structure Epitopes 46 3.8.2.1 Bcl?46
