Exploiting Chemical Diversity for Drug Discovery (eBook)

Part One: 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; 3: Automated PASP Synthesis of Biologically Active Molecules; 4: Flow Chemistry and Automation in the Synthesis of Drug-Like Molecules; 5: Conclusion; 6: References; Chapter 2: Accelerated Chemistry: Microwave, Sonochemical, and Fluorous Phase Techniques; 1: Introduction; 2: Microwave Enhanced Chemistry; 3: Sonochemistry as a Means to Accelerate Synthesis; 4: Fluorous Phase Techniques; 5: Conclusion; 6: References; Part Two: Conceptual Advances in Synthesis; Chapter 3: Biosynthesis of "Unnatural" Natural Products; 1: Introduction; 2: Type I Polyketide Synthases; 3: Type II Polyketide Synthases; 4: Type III Polyketide Synthase; 5: Conclusions; 6: Acknowledgements; 7: References; Chapter 4: Vombinatorial Synthetic Design: the Balance of Novelty and Familiarity; 1: Biological Macromolecules - Strength in Numbers; 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 Re-invent the Wheel?; 10: From Natural Products to Natural Product-like Libraries - Hubris or Progress?; 11: Lead Discovery and Combinatorial Chemistry - What Have we Learned?; 12: References; Chapter 5: Compound Collections: Acquisition, Annotation, and Access; 1: Introduction; 2: Commercial Offerings; 3: Companies Providing Non-proprietry, Non-parallel Synthesised Libraries (Shared-pool/"Collected Collections"); 4: Companies Providing In-house Designed, Parallel Synthesised Libraries; 5: Compound Selection and Database Filtering; 6: Substructure Similarity/Dissimilarity; 7: Pharmacophore Analysis; 8: Lipinski Rule-of-Five (LRoF); 9: Topological Polar Surface Area (tPSA) and Blood-Brain-Barrier Permeability (LogBB); 10: Solubility; 11: Examples of the Use of Chemical Annotation and Pharmacophore based lead-hopping; 12: Compound Acquisition; 13: References; Chapter 6: Chemical Diversity: Definition and Quantification; 1: Introduction; 2: Diversity Metrics; 3: Molecular Description; 4: Dimensionality Reduction; 5: Subset Selection and Classification; 6: Conclusion; 7: Abbreviations; 8: References; Part Three: 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; 3: Library Design Concepts; 4: Focused libraries; 5: Summary; 6: 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: References; Part Four: Operational Developments in Screening; Chapter 9: High Density Plates, Microarrays, Microfluidics; 1: Functional High-density Well Plates for High-throughput Assays; 2: Parallel Liquid Handling of Low-volume Samples; 3: Microarray Assays on Chips; 4: Prospects for Multi-Parameter Assays; 5: References; Chapter 10: Fluorescence Technologies for the Investigation of Chemical Libraries; 1: Introduction; 2: Dissociation Enhanced Lanthanide Fluoroimmunoassay (DELFIA); 3: Enzyme Fragment Complementation (EFC); 4: Fluorescence Polarization (FP); 5: Fluorescence Correlation Spectroscopy (FCS); 6: Amplified Luminescent Proximity Homogeneous Assay (Alphascreen); 7: Fluorescence Resonance Energy Transfer (FRET); 8: Bioluminescence Resonance Energy Transfer (BRET); 9: Homogeneous Time Resolved Fluorescence (HTRF); 10: Conclusion; 11: 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; 3: Reporter-based Assays; 4: Assays to Measure Intracellular Calcium; 5: Assays to Monitor Protein-Protein Interactions; 6: Conclusions and Outlook; 7: References; Chapter 12: NMR Based Screening, a Powerful Tool in Fragment-based Drug Discovery; 1: Introduction; 2: NMR Screening: General Aspects; 3: Ligand- vs Traget-detected Methods; 4: Incorporation of NMR into the Drug Discovery Process; 5: Representative Case Studies; 6: Conclusion; 7: References; Chapter 13: Screening Chemical Microarrays: Methods and Applications; 1: Introduction; 2: Screening of Chemical Microarrays; 3: Applications of Chemical Microarrays; 4: Conclusion; 5: References; Part Five: Conceptual Advances in Lead Evaluation; Chapter 14: Screen/Counter-screen: Early Assessment of Selectivity; 1: Introduction; 2: Approaches Used for Selection of Drug Candidates; 3: Summary; 4: References; Chapter 15: Concepts for in-vitro Profiling - Drug Activity, Selectivity and Liability; 1: Introduction; 2: Physico Chemical Parameters; 3: Permeability; 4: Metabolism; 5: Protein Binding; 6: Toxicity; 7: Investigation of Compound Selectivity; 8: Conclusion and Outlook; 9: Reference; Chapter 16: In silico Surrogates for in vivo Properties: Profiling for ADME and Toxicological Behavior; 1: In silico Surrogates for in vivo Properties; 2: Estimation of Biopharmaceutical Properties; 3: Estimation of Pharmacokinetic Properties; 4: Estimation of Toxicological Properties; 5: Integration of Surrogate Data and Estimations with Physiological Simulation; 6: References; Chapter 17: Use of High Content Screening in Chemical Optimization; 1: Introduction; 2: HCS Systems; 3: Examples Show the Power of HCS; 4: Summary