Chemical Biology: and Drug Discovery

Description

The focus of this textbook is on application, rather than pure knowledge transfer of the results of all chemical biological work (which would also be beyond the scope of a book). It gives the reader, through the specific selection of chemical biological techniques and concepts, the necessary tools to be able to develop new ways of thinking and thus new therapeutic options in the complex field of chemical biology and drug development. The stated aim of this book is to provide concrete solutions and inspiration to students, (post)graduate students, and experienced scientists at universities as well as in industry in their problems.  After an introduction to the problems addressed by chemical biology in drug discovery, the three levels of molecular biology dogma: DNA, RNA and proteins and their role as drug targets serve as the common thread of this book. This book is a translation of the original German 1st edition Chemische Biologie by Marco F. Schmidt, published by Springer-Verlag GmbH Germany, part of Springer Nature in 2020. The translation was done with the help of artificial intelligence (machine translation by the service DeepL.com). A subsequent human revision was done primarily in terms of content, so that the book will read stylistically differently from a conventional translation. Springer Nature works continuously to further the development of tools for the production of books and on the related technologies to support the authors. Preface Who Is the Book for? Contents 1: Introduction Part I: Chemical Biology and Drug Discovery 2: Chemical Biology: A Holistic Science 2.1 Reductionism and Holism in the Life Sciences 2.2 Chemical Biology Is Not Drug Development Further Reading 3: Drug Development 3.1 Drug Development 3.1.1 Search for Hit Molecule 3.1.2 Lead Structure Development and Preclinical Studies 3.1.3 Phase I Clinical Trial 3.1.4 Phase II Clinical Trial 3.1.5 Phase III Clinical Trial 3.2 Reasons for the Failure of Drug Development 3.3 The Gap Between Laboratory Experiments and Clinical Effect Further Reading 4: From Genomic Research to Chemical Biology 4.1 Chemical Genomics: Identification of New Drug Targets 4.2 Chemical Proteomics: Characterization of the Drug Target 4.3 Chemical Genetics: Validation of the Drug Target Advantages of Chemical GeneticsVersus Genetic Knock-Out Experiments Disadvantages of Chemical GeneticsVersus Genetic Knock-Out Experiments 4.4 Chemical Biology Further Reading Part II: DNA 5: DNA: Blueprint of the Proteins 5.1 Function and Structure of DNA 5.2 Oligonucleotide Synthesis Overview 5.3 DNA Sequencing 5.3.1 Polymerase Chain Reaction-PCR Procedure 5.3.2 Sanger Termination Sequencing 5.3.3 Next Generation Sequencing 5.3.4 DNA Microarray 6: Genomic Variation Reference Allele 6.1 Genome-Wide Association Studies Example (by Alicia Martin, Stanford University) 6.2 Fine Mapping 6.3 Polygenic Risk Score 6.4 Drug Target Linkage 6.5 Phenomenon-Wide Association Study-PheWAS Further Reading 7: Gene Therapy and Genome Editing 7.1 Gene Therapy 7.2 Genome Editing Further Reading Part III: RNA 8: RNA: Information and Function Carrier 8.1 RNA Interference Further Reading 9: RNA Interference in Drug Development 9.1 Oligonucleotides as Chemical Probes: Antisense Further Reading Part IV: Proteins 10: Peptides and Proteins 10.1 Amino Acid Peptide Protein Overview Overview 10.2 Peptide Synthesis 10.2.1 Orthogonality of Protection Groups 10.2.2 Peptide Bond Formation 10.3 Solid-Phase Peptide Synthesis 10.3.1 Merrifield Synthesis 10.3.2 Fmoc SPPS General Protocol of Fmoc Solid-Phase Synthesis 10.4 Protein Synthesis 10.4.1 Native Chemical Ligation 10.4.2 Staudinger Ligation 10.4.3 Inteine 10.4.4 Sortase-Mediated Ligation 10.4.5 Recombinant Proteins 10.5 Post-Translational Modifications 10.6 Summary 11: Proteins as Drug Targets 11.1 Receptors Ion Channel-Bound (Ionotropic) Receptors Hormone-Linked (Metabotropic) G-Protein Coupled Receptors (G-Coupled Receptor: GPCR) Enzyme-Linked Receptors Core Receptors Ligand-Receptor Binding Agonists Allosteric Modulators Antagonists Inverse Agonists 11.2 Enzymes 11.2.1 Enzyme Classification Examples 11.2.2 Special Catalysis Mechanisms of Enzymes 11.3 Enzyme Kinetics Overview 11.4 Non-Michalis-Menten Kinetics 11.5 Enzyme Inhibition 11.5.1 Reversible Inhibition 11.5.2 Irreversible Inhibition 11.5.3 Slow-Binding Inhibitors Further Reading 12: Chemical Genomics: From Target Protein to Small Molecule Drug 12.1 The Concept of the Small Molecule Chemical Probe 12.2 Combinatorial Chemistry 12.2.1 Diversity-Oriented Synthesis (DOS) 12.3 High-Throughput Screening 12.3.1 Assay Design 12.3.2 Pan Assay Interfering Substances: PAINS 12.4 Fragment-Based Drug Development Overview 12.5 Template-Based Drug Development 12.5.1 Dynamic Combinatorial Chemistry 12.5.2 Tethering 12.5.3 Dynamic Ligation Screening (DLS) 12.5.4 Substrate Activity Screening (SAS) 12.6 Computer-Aided Drug Design Overview Excursus: Open-Source Tools Chemical Probe Design Further Reading 13: From Target Protein to Biologics 13.1 Peptides Overview 13.2 Stapled Peptides 13.3 Monoclonal Antibodies Excursus: Biosimilars and Generics-Wine and Lemonade 13.4 Aptamers Further Reading 14: Chemical Proteomics: From Chemical Probe to Target Protein 14.1 Affinity Chromatography 14.2 Polypharmacology 15: Chemical Genetics: Validation of the Drug Target by Elucidation of the Signaling Pathway 15.1 Thalidomide and Embryonic Malformation 15.2 FK506 and the Ca2+-Calcineurin Signaling Pathway Further Reading 16: Chemical Biology: Addressing New Drug Targets 16.1 Protein-Protein Interaction 16.2 Chemical-Induced Dimerization (CID) 16.3 Pharmacological Chaperones 16.4 Antibody-Drug Conjugates 16.5 Chimeric Antigen Receptor T-Cell Therapy: CAR-T 16.6 Hydrophobic Tagging for Targeted Protein Degradation: Halo Tag 16.7 Proteolysis Targeting Chimera: PROTAC 16.8 Old Drugs: New Indications Further Reading Index