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Modern Approaches in Drug Discovery.

By: Lesburg, Charles.
Contributor(s): Lesburg, Charles.
Material type: materialTypeLabelBookSeries: Issn Ser: Publisher: San Diego : Elsevier Science & Technology, 2018Copyright date: �2018Description: 1 online resource (340 pages).Content type: text Media type: computer Carrier type: online resourceISBN: 9780128153840.Subject(s): Pharmaceutical chemistry | Drugs-DesignGenre/Form: Electronic books.DDC classification: 615.19 Online resources: Click to View
Contents:
Front Cover -- Modern Approaches in Drug Discovery -- Copyright -- Contents -- Contributors -- Preface -- References -- Chapter One: Risk Management in Early Discovery Medicinal Chemistry -- 1. Introduction -- 2. Risk in Drug Discovery -- 3. Management of Risks in Drug Discovery -- 4. General Strategies for Managing Risks -- 4.1. Business Models for Managing Risk -- 4.2. The Four Pillars -- 4.3. The Five Dimensions of Drug Discovery Productivity -- 5. Our Four Pillars of Early Discovery Derisking -- 5.1. Right Library -- 5.1.1. Reactive Compounds -- 5.1.2. Solubility and Physiochemical Properties -- 5.1.3. Purity and Structure Analysis of the Library Compounds -- 5.2. Right Assays -- 5.2.1. Derisking Interferences Through Assay Design -- 5.2.2. Sources of Compound-Mediated Assay Interference -- 5.2.3. Bioactivity Confirmation -- 5.2.4. Assay Design to Mitigate Compound-Mediated Assay Interferences -- 5.2.5. Post-HTS Counter-Screens to Derisk Compound-Mediated Assay Interferences -- 5.3. Right Compounds -- 5.4. Right Series -- 6. Advanced Topics -- 6.1. Assessing Readout Susceptibility and Specificity -- 6.2. Risk From Irreproducible Results -- 7. Summary -- References -- Further Reading -- Chapter Two: Target Identification Using Chemical Probes -- 1. Introduction -- 2. Target Engagement Assays -- 2.1. Fluorescence Recovery After Photobleaching Assays -- 2.2. Bioluminescence Resonance Energy Transfer Assays -- 2.3. Enzyme Fragment Complementation (EFC) Assays -- 2.4. Cellular Thermal Shift Assays -- 2.5. Activity-Based Assays -- 2.6. Proteolysis Targeting Chimeras -- 3. Probe Screening in Patient-Derived Assays -- 3.1. Advantages of Patient-Derived Assays -- 3.2. Disadvantages of Patient-Derived Assays -- 3.3. Step by Step Guide for Hit Validation and Prioritization -- 3.3.1. Cellular Viability Assays -- 3.3.2. Phenotypic Assay Design.
3.3.3. Dose Responses and Control Compounds -- 3.3.4. Target Validation With Gene Modulating Techniques -- 3.3.5. Functional Assays for Validation -- 4. Case Studies -- 4.1. G9a/GLP Histone Methyl Transferase Inhibitors -- 4.2. BRD9 Bromodomain Inhibitors -- 4.3. Other Examples -- 4.3.1. CDK4 and Exportin Inhibitors -- 4.3.2. KRAS Binders -- 4.3.3. BTK Inhibitors -- 5. Summary and Outlook -- References -- Chapter Three: Mining the Microbiome for Drug Targets -- 1. Introduction -- 2. Sample Collection and Sequencing for MWAS -- 2.1. Controlling for Heterogeneity in the Cohort -- 2.2. Sample Preservation -- 2.2.1. Reagents for Room-Temperature Preservation of Metagenomic Samples -- 2.3. DNA Extraction -- 2.4. Considerations in Shotgun Sequencing -- 2.4.1. Reagents for Metagenomic Shotgun Sequencing -- 3. Identifying Potential Drug Targets -- 3.1. Pinpointing the Disease-Associated Microbial Taxa -- 3.1.1. Software or Algorithms -- 3.2. Mining the Gene Functions -- 3.2.1. Databases for Mining Gene Functions -- 4. Summary and Outlook -- References -- Chapter Four: Screening Library Design -- 1. Diversity in Screening Library Design -- 2. Methods -- 3. Case Studies -- 4. Natural Products for Screening Library Design -- 5. Library Design for Screening Fragments -- 6. Virtual Library Design -- 7. Creating a Screening Library -- 8. Final Thoughts -- References -- Chapter Five: Design of a Fragment-Screening Library -- 1. Introduction -- 2. Compiling a Dataset of Compounds -- 3. Calculating Properties and Selecting a Representative Set -- 4. Library Quality Control -- 5. Sample Storage and Preparation -- 6. 1D H NMR -- 7. H Water-LOGSY -- 8. Failure Rate -- 9. SPR Reference Surface Binding -- 10. Mixture Design -- 11. Conclusion -- References -- Chapter Six: Genetically Encoded Cyclic Peptide Libraries: From Hit to Lead and Beyond -- 1. Introduction.
2. SICLOPPS -- 3. mRNA Display -- 4. The Path From Peptide Hit to the Clinic -- 5. Conclusions -- References -- Chapter Seven: A Guide to Run Affinity Screens Using Differential Scanning Fluorimetry and Surface Plasmon Resonance Assays -- 1. Introduction -- 2. Protein Denaturation Assays in Hit Identification -- 2.1. Differential Scanning Fluorimetry -- 2.1.1. Assay Development -- 2.1.2. General Considerations About Selecting Assay Buffer, DSF Dye, Protein, and Instrumentation -- 2.1.3. Setting up a Primary DSF Screen -- 2.1.4. Assay Protocol to Test Compounds -- 2.1.4.1. Material -- 2.1.4.2. Preparation of Dye/Protein Mix -- 2.1.4.3. Preparation of Ready-to-Use DSF Assay Plate -- 2.1.4.4. Assay Assembly and Measurement -- 2.1.5. DSF Data Analysis -- 2.2. Other Protein Denaturation Methods -- 2.2.1. Differential Static Light Scattering -- 2.2.2. Isothermal Chemical Denaturation -- 3. SPR in Low Molecular Weight Compound Screening -- 3.1. SPR in LMW Affinity Screening -- 3.1.1. Clean Screen -- 3.1.1.1. Instrument and Sensor Chip Preparation -- 3.1.1.2. Running Buffer Preparation -- 3.1.1.3. Compound Plate Preparation -- 3.1.1.4. Instrument Operation -- 3.1.1.5. Data Analysis -- 3.1.2. Binding Level Screen -- 3.1.2.1. Instrument and Sensor Chip Preparation -- 3.1.2.2. Running Buffer Preparation -- 3.1.2.3. Compound Plate and Solvent Correction Preparation -- 3.1.2.4. Instrument Operation -- 3.1.2.5. Data Analysis -- 3.1.3. Affinity Screen Protocol -- 3.1.3.1. Compound Plate and Solvent Correction Preparation -- 3.1.3.2. Instrument Operation -- 3.1.3.3. Data Analysis -- 4. Conclusion -- Acknowledgments -- References -- Chapter Eight: Second-Harmonic Generation (SHG) for Conformational Measurements: Assay Development, Optimization, and Scr ... -- 1. Introduction -- 2. Technology Background -- 3. Assay Development -- 3.1. Before Starting.
3.1.1. Choosing the Surface -- 3.1.2. SHG Assay-Compatible Buffers -- 3.1.3. Choosing SHG Assay Controls -- 3.2. Labeling -- 3.2.1. General Considerations for Labeling: SE Chemistry -- 3.2.2. General Considerations for Labeling: Maleimide Chemistry -- 3.2.3. Labeling Protocol -- 3.2.4. Conjugate Characterization: Determining DoL -- 3.2.5. Fine-Tuning the Native Residue Labeling Reaction -- 3.2.6. Engineered Residue Labeling vs Native Residue Labeling -- 3.2.7. Labeling Oligonucleotides -- 3.3. Tethering -- 3.3.1. Preparing the Ni-NTA SLB Surface -- 3.3.2. Conjugate Deposition -- 4. Running an SHG Assay -- 5. SHG Assay Development: Example -- 6. Screening -- 6.1. Scale to Screen -- 6.2. Small Molecule/Fragment Screening Concentrations -- 6.3. Running the Screen -- 6.4. Hit Calling -- 6.5. Nuisance Compounds -- 6.6. Hit Validation -- References -- Chapter Nine: An Array-Based Ligand Discovery Platform for Proteins With Short Half-Lives -- 1. Introduction -- 2. Expression of Protein by IVT -- 2.1. IVT Protein Expression -- 2.1.1. Reagents -- 2.1.2. Equipment -- 2.1.3. Protocol -- 2.2. Target Protein Quantification and Stability Assessment -- 2.2.1. Target Protein Quantification -- 2.2.2. Target Stability Assessment -- 3. SMM Screening -- 3.1. SMM Manufacture -- 3.1.1. Selection of Glass Substrate -- 3.1.2. Inclusion of Small-Molecule Controls -- 3.2. Screening of Target Protein -- 3.2.1. Reagents -- 3.2.2. Equipment -- 3.2.3. Protocol -- 4. Analysis of SMM Screening Data -- 4.1. Defining SNR Values for Each Array Feature -- 4.2. Computing and Interpreting Screening Statistics -- 5. Iterative Optimization of SMM Screening Conditions -- 5.1. Counter-Screening -- 5.2. Optimization of Protein Concentration and Antibody-Based Detection -- 6. Summary -- Acknowledgments -- References.
Chapter Ten: High Content, Phenotypic Assays and Screens for Compounds Modulating Cellular Processes in Primary Neurons -- 1. Introduction -- 2. HCS for Compounds Increasing Mitochondrial Content, Elongation, and Improving Health -- 2.1. Labeling of Mitochondria in Primary Neurons -- 2.1.1. Fluorescent Dyes -- 2.1.2. Expression of Fluorescent Reporters -- 2.2. Culturing of Primary Neurons -- 2.2.1. Equipment and Tools -- 2.2.2. Buffers and Reagents -- 2.2.3. Procedure -- 2.2.4. Notes -- 2.3. Compound Transfer -- 2.3.1. Equipment and Tools -- 2.3.2. Buffers and Reagents -- 2.3.3. Procedure -- 2.3.4. Notes -- 2.4. Imaging -- 2.4.1. Equipment -- 2.4.2. Specifications and Settings -- 2.4.3. Notes -- 2.5. Automated Image Analysis -- 2.5.1. Step-By-Step Procedure for CellProfiler -- 2.5.2. Notes -- 2.6. Analyzing the Data -- 2.6.1. Individual Object Measurements of Cell-Level Data -- 2.6.2. Well-Level Data -- 2.6.3. Assay Performance and Hit Selection -- 2.6.4. Step-By-Step Data Analysis Procedure Using Four Fields/Well and Four Replicate Plates -- 2.6.5. Notes -- 3. Summary and Conclusions -- References -- Further Reading -- Chapter Eleven: Achieving a Good Crystal System for Crystallographic X-Ray Fragment Screening -- 1. Introduction -- 2. Process Overview and Constraints on Crystals -- 3. Ways to Establish a Suitable Crystal System -- 3.1. Crystallization -- 3.2. Seeding -- 3.3. Protein Engineering -- 3.4. Test for Transferability -- 4. Common Problems -- 4.1. Poor Reproducibility -- 4.2. Poor X-Ray Diffraction Consistency -- 4.3. Difficulties With Crystallization Format -- 4.4. Drop Issues -- 4.5. Poor Soaking Tolerance -- 4.6. High Salt Conditions -- 5. Map and Model Considerations -- 6. Conclusion -- References -- Chapter Twelve: Hit-to-Lead: Hit Validation and Assessment -- 1. Introduction -- 2. Hit Assessment and Prioritization.
2.1. Hit Quality Assessment.
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Front Cover -- Modern Approaches in Drug Discovery -- Copyright -- Contents -- Contributors -- Preface -- References -- Chapter One: Risk Management in Early Discovery Medicinal Chemistry -- 1. Introduction -- 2. Risk in Drug Discovery -- 3. Management of Risks in Drug Discovery -- 4. General Strategies for Managing Risks -- 4.1. Business Models for Managing Risk -- 4.2. The Four Pillars -- 4.3. The Five Dimensions of Drug Discovery Productivity -- 5. Our Four Pillars of Early Discovery Derisking -- 5.1. Right Library -- 5.1.1. Reactive Compounds -- 5.1.2. Solubility and Physiochemical Properties -- 5.1.3. Purity and Structure Analysis of the Library Compounds -- 5.2. Right Assays -- 5.2.1. Derisking Interferences Through Assay Design -- 5.2.2. Sources of Compound-Mediated Assay Interference -- 5.2.3. Bioactivity Confirmation -- 5.2.4. Assay Design to Mitigate Compound-Mediated Assay Interferences -- 5.2.5. Post-HTS Counter-Screens to Derisk Compound-Mediated Assay Interferences -- 5.3. Right Compounds -- 5.4. Right Series -- 6. Advanced Topics -- 6.1. Assessing Readout Susceptibility and Specificity -- 6.2. Risk From Irreproducible Results -- 7. Summary -- References -- Further Reading -- Chapter Two: Target Identification Using Chemical Probes -- 1. Introduction -- 2. Target Engagement Assays -- 2.1. Fluorescence Recovery After Photobleaching Assays -- 2.2. Bioluminescence Resonance Energy Transfer Assays -- 2.3. Enzyme Fragment Complementation (EFC) Assays -- 2.4. Cellular Thermal Shift Assays -- 2.5. Activity-Based Assays -- 2.6. Proteolysis Targeting Chimeras -- 3. Probe Screening in Patient-Derived Assays -- 3.1. Advantages of Patient-Derived Assays -- 3.2. Disadvantages of Patient-Derived Assays -- 3.3. Step by Step Guide for Hit Validation and Prioritization -- 3.3.1. Cellular Viability Assays -- 3.3.2. Phenotypic Assay Design.

3.3.3. Dose Responses and Control Compounds -- 3.3.4. Target Validation With Gene Modulating Techniques -- 3.3.5. Functional Assays for Validation -- 4. Case Studies -- 4.1. G9a/GLP Histone Methyl Transferase Inhibitors -- 4.2. BRD9 Bromodomain Inhibitors -- 4.3. Other Examples -- 4.3.1. CDK4 and Exportin Inhibitors -- 4.3.2. KRAS Binders -- 4.3.3. BTK Inhibitors -- 5. Summary and Outlook -- References -- Chapter Three: Mining the Microbiome for Drug Targets -- 1. Introduction -- 2. Sample Collection and Sequencing for MWAS -- 2.1. Controlling for Heterogeneity in the Cohort -- 2.2. Sample Preservation -- 2.2.1. Reagents for Room-Temperature Preservation of Metagenomic Samples -- 2.3. DNA Extraction -- 2.4. Considerations in Shotgun Sequencing -- 2.4.1. Reagents for Metagenomic Shotgun Sequencing -- 3. Identifying Potential Drug Targets -- 3.1. Pinpointing the Disease-Associated Microbial Taxa -- 3.1.1. Software or Algorithms -- 3.2. Mining the Gene Functions -- 3.2.1. Databases for Mining Gene Functions -- 4. Summary and Outlook -- References -- Chapter Four: Screening Library Design -- 1. Diversity in Screening Library Design -- 2. Methods -- 3. Case Studies -- 4. Natural Products for Screening Library Design -- 5. Library Design for Screening Fragments -- 6. Virtual Library Design -- 7. Creating a Screening Library -- 8. Final Thoughts -- References -- Chapter Five: Design of a Fragment-Screening Library -- 1. Introduction -- 2. Compiling a Dataset of Compounds -- 3. Calculating Properties and Selecting a Representative Set -- 4. Library Quality Control -- 5. Sample Storage and Preparation -- 6. 1D H NMR -- 7. H Water-LOGSY -- 8. Failure Rate -- 9. SPR Reference Surface Binding -- 10. Mixture Design -- 11. Conclusion -- References -- Chapter Six: Genetically Encoded Cyclic Peptide Libraries: From Hit to Lead and Beyond -- 1. Introduction.

2. SICLOPPS -- 3. mRNA Display -- 4. The Path From Peptide Hit to the Clinic -- 5. Conclusions -- References -- Chapter Seven: A Guide to Run Affinity Screens Using Differential Scanning Fluorimetry and Surface Plasmon Resonance Assays -- 1. Introduction -- 2. Protein Denaturation Assays in Hit Identification -- 2.1. Differential Scanning Fluorimetry -- 2.1.1. Assay Development -- 2.1.2. General Considerations About Selecting Assay Buffer, DSF Dye, Protein, and Instrumentation -- 2.1.3. Setting up a Primary DSF Screen -- 2.1.4. Assay Protocol to Test Compounds -- 2.1.4.1. Material -- 2.1.4.2. Preparation of Dye/Protein Mix -- 2.1.4.3. Preparation of Ready-to-Use DSF Assay Plate -- 2.1.4.4. Assay Assembly and Measurement -- 2.1.5. DSF Data Analysis -- 2.2. Other Protein Denaturation Methods -- 2.2.1. Differential Static Light Scattering -- 2.2.2. Isothermal Chemical Denaturation -- 3. SPR in Low Molecular Weight Compound Screening -- 3.1. SPR in LMW Affinity Screening -- 3.1.1. Clean Screen -- 3.1.1.1. Instrument and Sensor Chip Preparation -- 3.1.1.2. Running Buffer Preparation -- 3.1.1.3. Compound Plate Preparation -- 3.1.1.4. Instrument Operation -- 3.1.1.5. Data Analysis -- 3.1.2. Binding Level Screen -- 3.1.2.1. Instrument and Sensor Chip Preparation -- 3.1.2.2. Running Buffer Preparation -- 3.1.2.3. Compound Plate and Solvent Correction Preparation -- 3.1.2.4. Instrument Operation -- 3.1.2.5. Data Analysis -- 3.1.3. Affinity Screen Protocol -- 3.1.3.1. Compound Plate and Solvent Correction Preparation -- 3.1.3.2. Instrument Operation -- 3.1.3.3. Data Analysis -- 4. Conclusion -- Acknowledgments -- References -- Chapter Eight: Second-Harmonic Generation (SHG) for Conformational Measurements: Assay Development, Optimization, and Scr ... -- 1. Introduction -- 2. Technology Background -- 3. Assay Development -- 3.1. Before Starting.

3.1.1. Choosing the Surface -- 3.1.2. SHG Assay-Compatible Buffers -- 3.1.3. Choosing SHG Assay Controls -- 3.2. Labeling -- 3.2.1. General Considerations for Labeling: SE Chemistry -- 3.2.2. General Considerations for Labeling: Maleimide Chemistry -- 3.2.3. Labeling Protocol -- 3.2.4. Conjugate Characterization: Determining DoL -- 3.2.5. Fine-Tuning the Native Residue Labeling Reaction -- 3.2.6. Engineered Residue Labeling vs Native Residue Labeling -- 3.2.7. Labeling Oligonucleotides -- 3.3. Tethering -- 3.3.1. Preparing the Ni-NTA SLB Surface -- 3.3.2. Conjugate Deposition -- 4. Running an SHG Assay -- 5. SHG Assay Development: Example -- 6. Screening -- 6.1. Scale to Screen -- 6.2. Small Molecule/Fragment Screening Concentrations -- 6.3. Running the Screen -- 6.4. Hit Calling -- 6.5. Nuisance Compounds -- 6.6. Hit Validation -- References -- Chapter Nine: An Array-Based Ligand Discovery Platform for Proteins With Short Half-Lives -- 1. Introduction -- 2. Expression of Protein by IVT -- 2.1. IVT Protein Expression -- 2.1.1. Reagents -- 2.1.2. Equipment -- 2.1.3. Protocol -- 2.2. Target Protein Quantification and Stability Assessment -- 2.2.1. Target Protein Quantification -- 2.2.2. Target Stability Assessment -- 3. SMM Screening -- 3.1. SMM Manufacture -- 3.1.1. Selection of Glass Substrate -- 3.1.2. Inclusion of Small-Molecule Controls -- 3.2. Screening of Target Protein -- 3.2.1. Reagents -- 3.2.2. Equipment -- 3.2.3. Protocol -- 4. Analysis of SMM Screening Data -- 4.1. Defining SNR Values for Each Array Feature -- 4.2. Computing and Interpreting Screening Statistics -- 5. Iterative Optimization of SMM Screening Conditions -- 5.1. Counter-Screening -- 5.2. Optimization of Protein Concentration and Antibody-Based Detection -- 6. Summary -- Acknowledgments -- References.

Chapter Ten: High Content, Phenotypic Assays and Screens for Compounds Modulating Cellular Processes in Primary Neurons -- 1. Introduction -- 2. HCS for Compounds Increasing Mitochondrial Content, Elongation, and Improving Health -- 2.1. Labeling of Mitochondria in Primary Neurons -- 2.1.1. Fluorescent Dyes -- 2.1.2. Expression of Fluorescent Reporters -- 2.2. Culturing of Primary Neurons -- 2.2.1. Equipment and Tools -- 2.2.2. Buffers and Reagents -- 2.2.3. Procedure -- 2.2.4. Notes -- 2.3. Compound Transfer -- 2.3.1. Equipment and Tools -- 2.3.2. Buffers and Reagents -- 2.3.3. Procedure -- 2.3.4. Notes -- 2.4. Imaging -- 2.4.1. Equipment -- 2.4.2. Specifications and Settings -- 2.4.3. Notes -- 2.5. Automated Image Analysis -- 2.5.1. Step-By-Step Procedure for CellProfiler -- 2.5.2. Notes -- 2.6. Analyzing the Data -- 2.6.1. Individual Object Measurements of Cell-Level Data -- 2.6.2. Well-Level Data -- 2.6.3. Assay Performance and Hit Selection -- 2.6.4. Step-By-Step Data Analysis Procedure Using Four Fields/Well and Four Replicate Plates -- 2.6.5. Notes -- 3. Summary and Conclusions -- References -- Further Reading -- Chapter Eleven: Achieving a Good Crystal System for Crystallographic X-Ray Fragment Screening -- 1. Introduction -- 2. Process Overview and Constraints on Crystals -- 3. Ways to Establish a Suitable Crystal System -- 3.1. Crystallization -- 3.2. Seeding -- 3.3. Protein Engineering -- 3.4. Test for Transferability -- 4. Common Problems -- 4.1. Poor Reproducibility -- 4.2. Poor X-Ray Diffraction Consistency -- 4.3. Difficulties With Crystallization Format -- 4.4. Drop Issues -- 4.5. Poor Soaking Tolerance -- 4.6. High Salt Conditions -- 5. Map and Model Considerations -- 6. Conclusion -- References -- Chapter Twelve: Hit-to-Lead: Hit Validation and Assessment -- 1. Introduction -- 2. Hit Assessment and Prioritization.

2.1. Hit Quality Assessment.

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Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, 2020. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries.

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