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Contents

Preface to the First Edition. Preface to the Second Edition. Acknowledgements. Abbreviations. 1 An introduction to drugs, their action and discovery. 1.1 Introduction. 1.2 What are drugs and why do we need new ones? 1.3 Drug discovery and design: a historical outline. 1.4 Leads and analogues: some desirable properties. 1.5 Sources of leads and drugs. 1.6 Methods and routes of administration: the pharmaceutical phase. 1.7 Introduction to drug action. 1.8 Classification of drugs. 1.9 Questions. 2 Drug structure and solubility. 2.1 Introduction. 2.2 Structure. 2.3 Stereochemistry and drug design. 2.3.1 Structurally rigid groups. 2.3.2 Conformation. 2.3.3 Configuration. 2.4 Solubility. 2.4.1 Solubility and the physical nature of the solute. 2.5 Solutions. 2.6 The importance of water solubility. 2.7 Solubility and the structure of the solute. 2.8 Salt formation. 2.9 The incorporation of water solubilising groups in a structure. 2.10 Formulation methods of improving water solubility. 2.11 The effect of pH on the solubility of acidic and basic drugs. 2.12 Partition. 2.13 Surfactants and amphiphiles. 2.14 Questions. 3 Structure-activity and quantitative structure relationships. 3.1 Introduction. 3.2 Structure-activity relationship (SAR). 3.3 Changing size and shape. 3.4 Introduction of new substituents. 3.5 Changing the existing substituents of a lead. 3.6 Case study: a SAR investigation to discover potent geminal bisphosphonates. 3.7 Quantitative structure-activity relationship (QSAR). 3.8 Questions. 4 Computer-aided drug design. 4.1 Introduction. 4.1.1 Models. 4.2 Molecular mechanics. 4.3 Molecular dynamics. 4.4 Quantum mechanics. 4.5 Docking. 4.6 Comparing three-dimensional structures by the use of overlays. 4.7 Pharmacophores and some of their uses. 4.8 Modelling protein structures. 4.9 Three-dimensional QSAR. 4.10 Other uses of computers in drug discovery. 4.11 Questions. 5 Combinatorial chemistry. 5.1 Introduction. 5.2 The solid support method. 5.3 Encoding methods. 5.4 Combinatorial synthesis in solution. 5.5 Deconvolution. 5.6 High-throughput screening (HTS). 5.7 Automatic methods of library generation and analysis. 5.8 Questions. 6 Drugs from natural sources. 6.1 Introduction. 6.2 Bioassays. 6.3 Dereplication. 6.4 Structural analysis of the isolated substance. 6.5 Active compound development. 6.6 Extraction procedures. 6.7 Fractionation methods. 6.8 Case history: the story of Taxol. 6.9 Questions. 7 Biological membranes. 7.1 Introduction. 7.2 The plasma membrane. 7.3 The transfer of species through cell membranes. 7.4 Drug action that affects the structure of cell membranes and walls. 7.5 Questions. 8 Receptors and messengers. 8.1 Introduction. 8.2 The chemical nature of the binding of ligands to receptors. 8.3 Structure and classification of receptors. 8.4 General mode of operation. 8.5 Ligand-response relationships. 8.6 Ligand-receptor theories. 8.7 Drug action and design. 8.8 Questions. 9 Enzymes. 9.1 Introduction. 9.2 Classification and nomenclature. 9.3 Active sites and catalytic action. 9.4 Regulation of enzyme activity. 9.5 The specific nature of enzyme action. 9.6 The mechanisms of enzyme action. 9.7 The general physical factors affecting enzyme action. 9.8 Enzyme kinetics. 9.9 Enzyme inhibitors. 9.10 Transition state inhibitors. 9.11 Enzymes and drug design: some general considerations. 9.12 Examples of drugs used as enzyme inhibitors. 9.13 Enzymes and drug resistance. 9.14 Ribozymes. 9.15 Questions. 10 Nucleic acids. 10.1 Introduction. 10.2 Deoxyribonucleic acid (DNA). 10.3 The general functions of DNA. 10.4 Genes. 10.5 Replication. 10.6 Ribonucleic acid (RNA). 10.7 Messenger RNA (mRNA). 10.8 Transfer RNA (tRNA). 10.9 Ribosomal RNA (rRNA). 10.10 Protein synthesis. 10.11 Protein synthesis in prokaryotic and eukaryotic cells. 10.12 Bacterial protein synthesis inhibitors (antimicrobials). 10.13 Drugs that target nucleic acids. 10.14 Viruses. 10.15 Recombinant DNA technology (genetic engineering). 10.16 Questions. 11 Pharmacokinetics. 11.1 Introduction. 11.2 Drug concentration analysis and its therapeutic significance. 11.3 Pharmacokinetic models. 11.4 Intravascular administration. 11.5 Extravascular administration. 11.6 The use of pharmacokinetics in drug design. 11.7 Extrapolation of animal experiments to humans. 11.8 Questions. 12 Drug metabolism. 12.1 Introduction. 12.2 Secondary pharmacological implications of metabolism. 12.2.4 Toxic metabolites. 12.3 Sites of action. 12.4 Phase I metabolic reactions. 12.5 Examples of Phase I metabolic reactions. 12.6 Phase II metabolic routes. 12.7 Pharmacokinetics of metabolites. 12.8 Drug metabolism and drug design. 12.9 Prodrugs. 12.10 Questions. 13 Complexes and chelating agents. 13.1 Introduction. 13.2 The shapes and structures of complexes. 13.3 Metal-ligand affinities. 13.4 The general roles of metal complexes in biological processes. 13.5 Therapeutic uses. 13.6 Drug action and metal chelation. 13.7 Questions. 14 Nitric oxide. 14.1 Introduction. 14.2 The structure of nitric oxide. 14.3 The chemical properties of nitric oxide. 14.4 The cellular production and role of nitric oxide. 14.5 The role of nitric oxide in physiological and pathophysiological states. 14.6 Therapeutic possibilities. 14.7 Questions. 15 An introduction to drug and analogue synthesis. 15.1 Introduction. 15.2 Some general considerations. 15.3 Asymmetry in syntheses. 15.4 Designing organic syntheses. 15.5 Partial organic synthesis of xenobiotics. 15.6 Questions. 16 Drug development and production. 16.1 Introduction. 16.2 Chemical development. 16.3 Pharmacological and toxicological testing. 16.4 Drug metabolism and pharmacokinetics. 16.5 Formulation development. 16.6 Production and quality control. 16.7 Patent protection. 16.8 Regulation. 16.9 Questions. Selected further reading. Answers to questions. Index.

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