Keywords:
Combinatorial chemistry.
;
Drugs -- Design.
;
Electronic books.
Description / Table of Contents:
This book examines the many aspects of the drug discovery process and presents the current state-of-the-art and a clear overview of approaches to lead identification.
Type of Medium:
Online Resource
Pages:
1 online resource (445 pages)
Edition:
1st ed.
ISBN:
9781847552556
Series Statement:
ISSN ; v.2
URL:
https://ebookcentral.proquest.com/lib/geomar/detail.action?docID=1185503
DDC:
572
Language:
English
Note:
Exploiting Chemical Diversity For Drug Discovery -- Contents -- Section 1 Operational Developments in Chemistry -- Chapter 1 The Use of Polymer-Assisted Solution-Phase Synthesis and Automation for the High-Throughput Preparation of Biologically Active Compounds -- 1 Introduction -- 2 PASP Synthesis Approaches to Biologically Active Compounds -- 2.1 Applications to the Synthesis of Commercial Drug Molecules -- 2.2 Applications of PASP to the Synthesis of Biologically Active Natural Products -- 2.3 PASP Synthesis in the Library Production of Biologically Active Small Molecules -- 3 Automated PASP Synthesis of Biologically Active Molecules -- 3.1 Stepwise Automation of PASP Synthesis in Batch Mode -- 3.2 Fully Automated PASP Synthesis of Drug-Like Molecules in Batch Mode -- 3.3 Flow Chemistry and Automation in the Synthesis of Drug-Like Molecules -- 4 Conclusion -- References -- Chapter 2 Accelerated Chemistry: Microwave, Sonochemical, and Fluorous Phase Techniques -- 1 Introduction -- 2 Microwave Enhanced Chemistry -- 2.1 General -- 2.2 Applications in Medicinal Chemistry -- 2.3 Applications in Solid-Phase Chemistry -- 3 Sonochemistry as a Means to Accelerate Synthesis -- 3.1 General -- 3.2 Organometallic Sonochemistry -- 3.3 Heterocyclic and Pericyclic Chemistry -- 3.4 Applications in Medicinal Chemistry -- 4 Fluorous Phase Techniques -- 4.1 General -- 4.2 Reagents, Linkers, and Scavengers -- 4.3 Fluorous Protecting Groups -- 4.4 Fluorous Mixture Synthesis -- 4.5 Peptides and Oligosaccharides -- 4.6 Fluorous Applications in High-Throughput Chemistry -- 4.7 Microwave-Enhanced Fluorous Chemistry -- 5 Conclusion -- Acknowledgements -- References -- Section 2 Conceptual Advances in Synthesis: "Prospecting" - Design of Discovery Libraries and the Search for Hits -- Chapter 3 Biosynthesis of "Unnatural" Natural Products -- 1 Introduction.
,
1.1 Polyketide Assembly -- 1.2 Three Major Classes of Polyketide Synthases -- 1.3 Methods for Engineered Biosynthesis -- 2 Type I Polyketide Synthases -- 2.1 Modular Architecture -- 2.2 The Erythromycin Synthase -- 2.3 Engineered Biosynthesis of Multimodular PKS Products -- 2.3.1 Domain Engineering -- 2.3.2 Module Engineering -- 2.3.3 Primer Unit Engineering and Precursor-Directed Biosynthesis -- 2.4 Multimodular PKSs that Exhibit Special Features -- 2.5 Fungal Type I PKSs -- 3 Type II Polyketide Synthases -- 3.1 Dissociated Architecture -- 3.2 Combinatorial Biosynthesis of Type II Polyketides -- 3.2.1 Chain-Length Variations -- 3.2.2 Mix and Match of Tailoring Enzymes -- 3.2.3 Primer Unit Modifications -- 3.2.4 Reshuffling of DownstreamTailoring Enzymes -- 4 Type III Polyketide Synthase -- 4.1 Type III PKS Consists of a Homodimeric Ketosynthase -- 4.2 Engineered Biosynthesis of Type III Polyketides -- 5 Conclusions -- Acknowledgments -- References -- Chapter 4 Combinatorial Synthetic Design: The Balance of Novelty and Familiarity -- 1 Biological Macromolecules - Strength in Numbers -- 1.1 Congruence between Biological and Chemical Space -- 1.2 The Libraries are Exhaustive within the Defined Boundaries -- 1.3 Highly Optimized Synthesis Procedures were Available -- 2 Oligomer Synthesis - Improving on Mother Nature -- 3 Random, Discovery, or Prospecting Libraries - the Quest for the Universal Scaffold -- 4 Privileged Scaffolds - Look Where the Light is Brightest -- 5 The Decoration or Synthesis of Novel Scaffolds - Aid for the Underprivileged -- 6 Target Class Libraries - Diversity with a Purpose -- 7 Peptide and Nucleotide Libraries Redux -- 8 Lead Discovery or Drug Discovery - Size does Matter -- 9 Natural Product Scaffolds for Combinatorial Chemistry - Why Reinvent the Wheel?.
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10 From Natural Products to Natural Product-Like Libraries - Hubris or Progress? -- 11 Lead Discovery and Combinatorial Chemistry - What have We Learned? -- 11.1 The Drug-Discovery Process cannot be Simplified to a Single Blueprint -- 11.2 Combinatorial Chemistry is an Extremely Powerful Technology -- 11.3 Combinatorial Chemistry is at its Best in Lead Optimization -- 11.4 Combinatorial Chemistry is about Making the Compounds that Fit Your Needs, not How They are Made -- References -- Chapter 5 Compound Collections: Acquisition, Annotation, and Access -- 1 Introduction -- 2 Commercial Offerings -- 3 Companies Providing Non-Proprietary, Non-Parallel Synthesised Libraries (Shared-Pool/'Collected Collections') -- 4 Companies Providing In-House Designed, Parallel Synthesised Libraries -- 5 Compound Selection and Database Filtering -- 6 Sub-structure Similarity/Dissimilarity -- 7 Pharmacophore Analysis -- 8 Annotation -- 9 Lipinski Rule-of-Five (LRoF) -- 10 Topological Polar Surface Area (tPSA) and Blood-Brain-Barrier Permeability (Log BB) -- 11 Solubility -- 12 Examples of the Use of Chemical Annotation and Pharmacophore-Based Lead-Hopping -- 13 Compound Acquisition -- Acknowledgments -- References -- Chapter 6 Chemical Diversity: Definition and Quantification -- 1 Introduction -- 2 Diversity Metrics -- 2.1 Distance-Based Metrics -- 2.2 Cell-Base Diversity Metrics -- 2.3 Variance-Based Diversity Metrics -- 3 Molecular Description -- 3.1 Two-Dimensional Descriptors -- 3.2 Three-Dimensional Descriptors -- 3.3 Physicochemical and Electronic Descriptors -- 3.4 Descriptor Selection -- 4 Dimensionality Reduction -- 4.1 Principle Component Analysis -- 4.2 Singular-Value Decomposition -- 4.3 Factor Analysis (FA) -- 4.4 MultiDimensional Scaling -- 4.5 Stochastic Proximity Embedding -- 5 Subset Selection and Classification -- 5.1 Clustering.
,
5.2 Partitioning Methods -- 5.3 Experimental Design -- 5.4 Reagent-Based Versus Product-Based Design -- 5.5 Random Versus Rational Design -- 6 Conclusion -- Abbreviations -- References -- Section 3 Conceptual Advances in Synthesis: "Mining" - Turning a Hit into a Lead -- Chapter 7 Focused Libraries: The Evolution in Strategy from Large-Diversity Libraries to the Focused Library Approach -- 1 Introduction -- 2 A Synergistic, Multidisciplinary Approach to Library Conception -- 2.1 Improvements in Synthetic Methods -- 2.2 Impact of In Silico Tools for Library Design -- 2.3 Influence of Biology in Library Design -- 3 Library Design Concepts -- 3.1 Impact of Diversity on Library Design -- 3.2 Diversity-Oriented Synthesis in Prospecting Library Design -- 3.3 Target-Oriented Library Design -- 3.4 Focus on Drug-Like Libraries -- 4 Focused Libraries -- 4.1 Libraries Focused on Pharmacophore Models -- 4.2 Libraries Focused on Privileged Structures -- 4.3 Libraries Focused on Target Classes -- 4.3.1 GPCR-Targeted Libraries -- 4.3.2 Kinase-Targeted Libraries -- 4.3.3 Natural Product-Based Focused Libraries -- 4.4 Early Optimization or Hit-to-Lead Libraries -- 5 Summary -- References -- Chapter 8 Translating Peptides into Small Molecules -- 1 Peptides as Drugs: The Good, the Bad and the Ugly -- 2 Origin of Biologically Active Peptides -- 3 General Strategy for Translating Peptides into Small Molecules -- 4 Tailoring Peptide Sequences for their Translation into Small Molecules -- 5 Transformation of Peptide Ligands into Small Molecules using Computational Approaches -- 6 Conclusion -- References -- Section 4 Operational Developments in Screening and High Throughput Assays -- Chapter 9 High-Density Plates, Microarrays, Microfluidics -- 1 Functional High-Density Well Plates for High-Throughput Assays -- 1.1 Sample Plates for Low-Volume High-Throughput Screening.
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1.2 High-Density Assay Plates for HTS and Multidimensional Compound Profiling -- 1.3 Technical, Biological, and Economical Limits for Assay Miniaturization in High-Density Plates -- 1.4 384-Microtube Plate for High-Throughput Retrieval of Compound Subsets -- 1.5 Sample Management for HTS and Multidimensional Compound Profiling -- 2 Parallel Liquid Handling of Low-Volume Samples -- 2.1 Pipetting and Dispensing in High-Density Plates -- 2.2 High-Throughput Aliquoting of the HTS Library -- 2.3 A Microfluidic Well Plate for High-Throughput Solid/Liquid Separations -- 3 Microarray Assays on Chips -- 3.1 Microchannel Assay: A New Generation of Miniaturized Multiplexed Bioassays -- 4 Prospects for Multiparameter Assays -- Acknowledgment -- References -- Chapter 10 Fluorescence Technologies for the Investigation of Chemical Libraries -- 1 Introduction -- 2 Dissociation-Enhanced Lanthanide Fluoroimmunoassay -- 3 Enzyme Fragment Complementation -- 4 Fluorescence Polarization -- 5 Fluorescence Correlation Spectroscopy -- 6 Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen™) -- 7 Fluorescence Resonance Energy Transfer -- 8 Bioluminescence Resonance Energy Transfer -- 9 Homogeneous Time Resolved Fluorescence -- 10 Conclusion -- References -- Chapter 11 The Use of Genetically Engineered Cell-Based Assays in in-vitro Drug Discovery -- 1 Introduction -- 2 Genetic Engineering for Cell-Based Assays -- 2.1 Expression Systems -- 2.2 Choice of Cell Line and Promoter -- 2.3 Chromosomal Integration Site -- 3 Reporter-Based Assays -- 3.1 Chloramphenicol Acetyl Transferase, Secreted Placental Alkaline Phosphatase, β-Galactosidase -- 3.2 Green Fluorescent Protein -- 3.3 Luciferase -- 3.4 β-Lactamase -- 3.5 Examples of Applications -- 4 Assays to Measure Intracellular Calcium -- 5 Assays to Monitor Protein-Protein Interactions.
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5.1 Bioluminescence Resonance Energy Transfer and Fluorescence Resonance Energy Transfer.
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