Efnisyfirlit

• Cover
• Title Page
• Copyright page
• Preface
• About the Book
  • Emboldened key words
  • Boxes
  • Key points
  • Struggle Alert
  • Questions
  • Further reading
  • Appendix and glossary
  • Links
  • Disclaimer
• About Oxford Learning Link
  • Student resources
    • Multiple choice questions
    • Rotatable 3D structures
    • Web articles
    • Molecular modelling
    • Protein Data Bank
  • Lecturer resources
    • Test Bank
    • Answers
    • Figures from the book
    • PowerPoint slides
• Acknowledgements
• Table of Contents
• List of Boxes
  • General interest
  • Synthesis
  • Clinical correlation
• Acronyms and abbreviations
• 1 Drugs and drug targets: an overview
  • 1.1 What is a drug?
  • 1.2 Drug targets
    • 1.2.1 Cell structure
    • 1.2.2 Drug targets at the molecular level
  • 1.3 Intermolecular bonding forces
    • 1.3.1 Electrostatic or ionic bonds
    • 1.3.2 Hydrogen bonds
      • 1.3.2.1 Conventional hydrogen bonds
      • 1.3.2.2 Unconventional hydrogen bonds
    • 1.3.3 Van der Waals interactions
    • 1.3.4 Dipole–dipole, ion–dipole, and cation–π interactions
    • 1.3.5 π–π interactions
    • 1.3.6 Halogen bonds
    • 1.3.7 Repulsive interactions
    • 1.3.8 The role of water and hydrophobic interactions
  • 1.4 Pharmacokinetic issues and medicines
  • 1.5 Classification of drugs
    • 1.5.1 By pharmacological effect
    • 1.5.2 By chemical structure
    • 1.5.3 By target system
    • 1.5.4 By target molecule
  • 1.6 Naming of drugs and medicines
  • Questions
  • Further Reading
  • Websites
  • List of Key Terms
• Part A Drug targets: Structure and function
  • 2 Protein structure and function
    • 2.1 The primary structure of proteins
    • 2.2 The secondary structure of proteins
      • 2.2.1 The α-helix
      • 2.2.2 The β-pleated sheet
      • 2.2.3 The β-turn
    • 2.3 The tertiary structure of proteins
      • 2.3.1 Covalent bonds: disulphide links
      • 2.3.2 Ionic or electrostatic bonds
      • 2.3.3 Hydrogen bonds
      • 2.3.4 Van der Waals and hydrophobic interactions
      • 2.3.5 Relative importance of bonding interactions
      • 2.3.6 Role of the planar peptide bond
    • 2.4 The quaternary structure of proteins
    • 2.5 Translation and post-translational modifications
    • 2.6 Proteomics
    • 2.7 Protein function
      • 2.7.1 Structural proteins
      • 2.7.2 Transport proteins
      • 2.7.3 Enzymes and receptors
      • 2.7.4 Miscellaneous proteins and protein–protein interactions
    • Questions
    • Oxford Learning Link
    • Further Reading
    • List of Key Terms
  • 3 Enzymes: structure and function
    • 3.1 Enzymes as catalysts
    • 3.2 How do enzymes catalyse reactions?
    • 3.3 The active site of an enzyme
    • 3.4 Substrate binding at an active site
    • 3.5 The catalytic role of enzymes
      • 3.5.1 Binding interactions
      • 3.5.2 Acid/base catalysis
      • 3.5.3 Nucleophilic groups
      • 3.5.4 Stabilization of the transition state
      • 3.5.5 Cofactors
      • 3.5.6 Naming and classification of enzymes
      • 3.5.7 Genetic polymorphism and enzymes
    • 3.6 Regulation of enzymes
    • 3.7 Isozymes
    • 3.8 Enzyme kinetics
      • 3.8.1 The Michaelis–Menten equation
      • 3.8.2 Lineweaver–Burk plots
    • Questions
    • Further Reading
    • List of Key Terms
  • 4 Receptors: structure and function
    • 4.1 Role of the receptor
    • 4.2 Neurotransmitters and hormones
    • 4.3 Receptor types and subtypes
    • 4.4 Receptor activation
    • 4.5 How does the binding site change shape?
    • 4.6 Ion channel receptors
      • 4.6.1 General principles
      • 4.6.2 Structure
      • 4.6.3 Gating
      • 4.6.4 Ligand-gated and voltage-gated ion channels
    • 4.7 G-Protein-coupled receptors
      • 4.7.1 General principles
      • 4.7.2 Structure of G-protein-coupled receptors
      • 4.7.3 The rhodopsin-like family of G-protein-coupled receptors
      • 4.7.4 Dimerization of G-coupled receptors
    • 4.8 Kinase receptors
      • 4.8.1 General principles
      • 4.8.2 Structure of tyrosine kinase receptors
      • 4.8.3 Activation mechanism for tyrosine kinase receptors
      • 4.8.4 Tyrosine kinase receptors as targets in drug discovery
        • 4.8.4.1 The ErbB family of tyrosine kinase receptors
        • 4.8.4.2 Vascular endothelial growth factor receptors
        • 4.8.4.3 Platelet-derived growth factor receptors
        • 4.8.4.4 Stem cell growth factor receptors
        • 4.8.4.5 Anaplastic lymphoma kinase
        • 4.8.4.6 The RET receptor
        • 4.8.4.7 Hepatocyte growth factor receptor or c-MET receptor
    • 4.9 Intracellular receptors
    • 4.10 Regulation of receptor activity
    • 4.11 Genetic polymorphism and receptors
    • Questions
    • Further Reading
    • List of Key Terms
  • 5 Receptors and signal transduction
    • 5.1 Signal transduction pathways for G-protein-coupled receptors (GPCRs)
      • 5.1.1 Interaction of the receptor–ligand complex with G-proteins
      • 5.1.2 Signal transduction pathways involving the α-subunit
    • 5.2 Signal transduction involving G-proteins and adenylate cyclase
      • 5.2.1 Activation of adenylate cyclase by the αs-subunit
      • 5.2.2 Activation of protein kinase A
      • 5.2.3 The Gi-protein
      • 5.2.4 General points about the signalling cascade involving cyclic AMP
      • 5.2.5 The role of the βγ-dimer
      • 5.2.6 Phosphorylation
    • 5.3 Signal transduction involving G-proteins and phospholipase Cβ
      • 5.3.1 G-protein effect on phospholipase Cβ
      • 5.3.2 Action of the secondary messenger: diacylglycerol
      • 5.3.3 Action of the secondary messenger: inositol triphosphate
      • 5.3.4 Resynthesis of phosphatidylinositol diphosphate
    • 5.4 The role of β-arrestins in modulating the activity of G-protein-coupled receptors
    • 5.5 Signal transduction involving kinase receptors
      • 5.5.1 Activation of signalling proteins and enzymes
      • 5.5.2 The MAPK signal transduction pathway
      • 5.5.3 Activation of guanylate cyclase by kinase receptors
      • 5.5.4 The JAK-STAT signal transduction pathway
      • 5.5.5 The PI3K/Akt/mTOR signal transduction pathway
    • 5.6 The hedgehog signalling pathway
    • Questions
    • Further Reading
    • List of Key Terms
  • 6 Nucleic acids: structure and function
    • 6.1 Structure of DNA
      • 6.1.1 The primary structure of DNA
      • 6.1.2 The secondary structure of DNA
      • 6.1.3 The tertiary structure of DNA
      • 6.1.4 Chromatins
      • 6.1.5 Genetic polymorphism and personalized medicine
    • 6.2 Ribonucleic acid and protein synthesis
      • 6.2.1 Structure of RNA
      • 6.2.2 Transcription and translation
      • 6.2.3 Small nuclear RNA
      • 6.2.4 The regulatory role of RNA
    • 6.3 Genetic illnesses
    • 6.4 Molecular biology and genetic engineering
    • Questions
    • Further Reading
    • List of Key Terms
• Part B Pharmacodynamics and pharmacokinetics
  • 7 Enzymes as drug targets
    • 7.1 Inhibitors acting at the active site of an enzyme
      • 7.1.1 Reversible inhibitors
      • 7.1.2 Irreversible inhibitors
    • 7.2 Inhibitors acting at allosteric binding sites
    • 7.3 Uncompetitive and non-competitive inhibitors
    • 7.4 Transition-state analogues: renin inhibitors
    • 7.5 Suicide substrates
    • 7.6 Isozyme selectivity of inhibitors
    • 7.7 Medicinal uses of enzyme inhibitors
      • 7.7.1 Enzyme inhibitors used against microorganisms
      • 7.7.2 Enzyme inhibitors used against viruses
      • 7.7.3 Enzyme inhibitors used against the body’s own enzymes
      • 7.7.4 Enzyme modulators
    • 7.8 Enzyme kinetics
      • 7.8.1 Lineweaver–Burk plots
      • 7.8.2 Comparison of inhibitors
    • Questions
    • Further Reading
    • List of Key Terms
  • 8 Receptors as drug targets
    • 8.1 Introduction
    • 8.2 The design of agonists
      • 8.2.1 Binding groups
      • 8.2.2 Position of the binding groups
      • 8.2.3 Size and shape
      • 8.2.4 Other design strategies
      • 8.2.5 Pharmacodynamics and pharmacokinetics
      • 8.2.6 Examples of agonists
      • 8.2.7 Allosteric modulators
    • 8.3 The design of antagonists
      • 8.3.1 Antagonists acting at the binding site
      • 8.3.2 Antagonists acting outside the binding site
    • 8.4 Partial agonists
    • 8.5 Inverse agonists
    • 8.6 Desensitization and sensitization
    • 8.7 Tolerance and dependence
    • 8.8 Receptor types and subtypes
    • 8.9 Affinity, efficacy, and potency
    • Questions
    • Further Reading
    • List of Key Terms
  • 9 Nucleic acids as drug targets
    • 9.1 Intercalating drugs acting on DNA
    • 9.2 Topoisomerase poisons: non-intercalating
    • 9.3 Alkylating and metallating agents
      • 9.3.1 Nitrogen mustards
      • 9.3.2 Nitrosoureas
      • 9.3.3 Busulfan
      • 9.3.4 Cisplatin
      • 9.3.5 Dacarbazine and procarbazine
      • 9.3.6 Mitomycin C
    • 9.4 Chain cutters
    • 9.5 Chain terminators
    • 9.6 Control of gene transcription
    • 9.7 Agents that act on RNA
      • 9.7.1 Agents that bind to ribosomes
      • 9.7.2 Antisense therapy
    • Questions
    • Further Reading
    • List of Key Terms
  • 10 Miscellaneous drug targets
    • 10.1 Transport proteins as drug targets
    • 10.2 Structural proteins as drug targets
      • 10.2.1 Viral structural proteins as drug targets
      • 10.2.2 Tubulin as a drug target
        • 10.2.2.1 Agents that inhibit tubulin polymerization
        • 10.2.2.2 Agents that inhibit tubulin depolymerization
    • 10.3 Biosynthetic building blocks as drug targets
    • 10.4 Biosynthetic processes as drug targets: chain terminators
    • 10.5 Protein–protein interactions
      • 10.5.1 Inhibition of protein–protein interactions
      • 10.5.2 Promotion of protein–protein interactions
    • 10.6 Lipids as a drug target
      • 10.6.1 ‘Tunnelling molecules’
      • 10.6.2 Ion carriers
      • 10.6.3 Tethers and anchors
    • 10.7 Carbohydrates as drug targets
      • 10.7.1 Glycomics
      • 10.7.2 Antigens and antibodies
      • 10.7.3 Cyclodextrins
    • Questions
    • Further Reading
    • List of Key Terms
  • 11 Pharmacokinetics and related topics
    • 11.1 The three phases of drug action
    • 11.2 A typical journey for an orally active drug
    • 11.3 Drug absorption
    • 11.4 Drug distribution
      • 11.4.1 Distribution round the blood supply
      • 11.4.2 Distribution to tissues
      • 11.4.3 Distribution to cells
      • 11.4.4 Other distribution factors
      • 11.4.5 Blood–brain barrier
      • 11.4.6 Placental barrier
      • 11.4.7 Drug–drug interactions
    • 11.5 Drug metabolism
      • 11.5.1 Phase I and phase II metabolism
      • 11.5.2 Phase I transformations catalysed by cytochrome P450 enzymes
      • 11.5.3 Phase I transformations catalysed by flavin-containing monooxygenases
      • 11.5.4 Phase I transformations catalysed by other enzymes
      • 11.5.5 Phase II transformations
      • 11.5.6 Metabolic stability
      • 11.5.7 The first pass effect
    • 11.6 Drug excretion
    • 11.7 Drug administration
      • 11.7.1 Oral administration
      • 11.7.2 Absorption through mucous membranes
      • 11.7.3 Rectal administration
      • 11.7.4 Topical administration
      • 11.7.5 Inhalation
      • 11.7.6 Injection
      • 11.7.7 Implants
    • 11.8 Drug dosing
      • 11.8.1 Drug half-life
      • 11.8.2 Steady state concentration
      • 11.8.3 Drug tolerance
      • 11.8.4 Bioavailability
    • 11.9 Formulation
    • 11.10 Drug delivery
    • Questions
    • Further Reading
    • List of Key Terms
  • Case study 1 Statins
    • CS1.1 Cholesterol and coronary heart disease
    • CS1.2 The target enzyme
    • CS1.3 The discovery of statins
      • CS1.3.1 Type I statins
      • CS1.3.2 Type II statins
    • CS1.4 Mechanism of action for statins—pharmacodynamics
    • CS1.5 Binding interactions of statins
    • CS1.6 Other mechanisms of action for statins
    • CS1.7 Other targets for cholesterol-lowering drugs
    • Further Reading
• Part C Drug discovery, design, and development
  • 12 Drug discovery: finding a lead
    • 12.1 Choosing a disease
    • 12.2 Choosing a drug target
      • 12.2.1 Drug targets
      • 12.2.2 Discovering drug targets
      • 12.2.3 Target specificity and selectivity between species
      • 12.2.4 Target specificity and selectivity within the body
      • 12.2.5 Targeting drugs to specific organs and tissues
      • 12.2.6 Pitfalls
      • 12.2.7 Multi-target drugs
    • 12.3 Identifying a bioassay
      • 12.3.1 Choice of bioassay
      • 12.3.2 In vitro tests
      • 12.3.3 In vivo tests
      • 12.3.4 Test validity
      • 12.3.5 High-throughput screening
      • 12.3.6 Screening by NMR
      • 12.3.7 Affinity screening
      • 12.3.8 Surface plasmon resonance
      • 12.3.9 Scintillation proximity assay
      • 12.3.10 Isothermal titration calorimetry
      • 12.3.11 Virtual screening
    • 12.4 Finding a lead compound
      • 12.4.1 Screening of natural products
        • 12.4.1.1 The plant kingdom
        • 12.4.1.2 Microorganisms
        • 12.4.1.3 Marine sources
        • 12.4.1.4 Animal sources
        • 12.4.1.5 Venoms and toxins
      • 12.4.2 Medical folklore
      • 12.4.3 Screening synthetic compound ‘libraries’
      • 12.4.4 Existing drugs
        • 12.4.4.1 ‘Me too’ and ‘me better’ drugs
        • 12.4.4.2 Enhancing a side effect
      • 12.4.5 Starting from the natural ligand or modulator
        • 12.4.5.1 Natural ligands for receptors
        • 12.4.5.2 Natural substrates for enzymes
        • 12.4.5.3 Enzyme products as lead compounds
        • 12.4.5.4 Natural modulators as lead compounds
      • 12.4.6 Combinatorial and parallel synthesis
      • 12.4.7 Computer-aided design of lead compounds
      • 12.4.8 Serendipity and the prepared mind
      • 12.4.9 Computerized searching of structural databases
      • 12.4.10 Fragment-based lead discovery
      • 12.4.11 Properties of lead compounds
    • 12.5 Isolation and purification
    • 12.6 Structure determination
    • 12.7 Herbal medicine
    • Questions
    • Further Reading
    • List of Key Terms
  • 13 Drug design: optimizing target interactions
    • 13.1 Structure–activity relationships
      • 13.1.1 Binding role of alcohols and phenols
      • 13.1.2 Binding role of aromatic rings
      • 13.1.3 Binding role of alkenes
      • 13.1.4 Binding role of ketones and aldehydes
      • 13.1.5 Binding role of amines
      • 13.1.6 Binding role of amides
      • 13.1.7 Binding role of quaternary ammonium salts
      • 13.1.8 Binding role of carboxylic acids
      • 13.1.9 Binding role of esters
      • 13.1.10 Binding role of alkyl and aryl halides
      • 13.1.11 Binding role of thiols and ethers
      • 13.1.12 Binding role of phosphates, phosphonates, and phosphinates
      • 13.1.13 Binding role of other functional groups
      • 13.1.14 Binding role of alkyl groups and the carbon skeleton
      • 13.1.15 Binding role of heterocycles
      • 13.1.16 Isosteres
      • 13.1.17 Testing procedures
      • 13.1.18 SAR in drug optimization
    • 13.2 Identification of a pharmacophore
    • 13.3 Drug optimization: strategies in drug design
      • 13.3.1 Variation of substituents
        • 13.3.1.1 Alkyl substituents
        • 13.3.1.2 Substituents on aromatic or heteroaromatic rings
        • 13.3.1.3 Varying substituents to change the pKa of ionizable groups
        • 13.3.1.4 Synergistic effects
      • 13.3.2 Extension of the structure
      • 13.3.3 Chain extension/contraction
      • 13.3.4 Ring expansion/contraction
      • 13.3.5 Ring variations
      • 13.3.6 Ring fusions
      • 13.3.7 Isosteres and bio-isosteres
      • 13.3.8 Simplification of the structure
      • 13.3.9 Rigidification of the structure
      • 13.3.10 Conformational blockers
      • 13.3.11 Rigidification through intramolecular bonds
      • 13.3.12 Structure-based drug design and molecular modelling
      • 13.3.13 Drug design by NMR spectroscopy
      • 13.3.14 The elements of luck and inspiration
      • 13.3.15 Designing drugs to interact with more than one target
        • 13.3.15.1 Agents designed from known drugs
        • 13.3.15.2 Agents designed from non-selective lead compounds
    • 13.4 Selectivity
    • 13.5 Pharmacokinetics
    • Questions
    • Further Reading
    • List of Key Terms
  • 14 Drug design: optimizing access to the target
    • 14.1 Optimizing hydrophilic/hydrophobic properties
      • 14.1.1 Masking polar functional groups to decrease polarity
      • 14.1.2 Adding or removing polar functional groups to vary polarity
      • 14.1.3 Varying hydrophobic substituents to vary polarity
      • 14.1.4 Variation of N-alkyl substituents to vary pKa
      • 14.1.5 Other structural variations affecting pKa
      • 14.1.6 Bio-isosteres for polar groups involved in binding interactions
    • 14.2 Making drugs more resistant to chemical and enzymatic degradation
      • 14.2.1 Steric shields
      • 14.2.2 Electronic effects of bio-isosteres and substituents
      • 14.2.3 Steric and electronic modifications
      • 14.2.4 Metabolic blockers
      • 14.2.5 Removal or replacement of susceptible metabolic groups
      • 14.2.6 Group shifts
      • 14.2.7 Ring variation and ring substituents
    • 14.3 Making drugs less resistant to drug metabolism
      • 14.3.1 Introducing metabolically susceptible groups
      • 14.3.2 Self-destruct drugs
    • 14.4 Targeting drugs
      • 14.4.1 Targeting tumour cells: ‘search and destroy’ drugs
      • 14.4.2 Targeting gastrointestinal infections
      • 14.4.3 Targeting peripheral regions rather than the central nervous system
      • 14.4.4 Targeting with membrane tethers
      • 14.4.5 Targeting antibacterial agents using siderophores
    • 14.5 Reducing toxicity
    • 14.6 Prodrugs
      • 14.6.1 Prodrugs to improve membrane permeability
        • 14.6.1.1 Esters as prodrugs
        • 14.6.1.2 N-Methylated prodrugs
        • 14.6.1.3 Trojan horse approach for transport proteins
      • 14.6.2 Prodrugs to prolong drug activity
      • 14.6.3 Prodrugs masking drug toxicity and side effects
      • 14.6.4 Prodrugs to lower water solubility
      • 14.6.5 Prodrugs to improve water solubility
      • 14.6.6 Prodrugs used in the targeting of drugs
      • 14.6.7 Prodrugs to increase chemical stability
      • 14.6.8 Prodrugs activated by external influence (sleeping agents)
    • 14.7 Drug alliances
      • 14.7.1 ‘Sentry’ drugs
      • 14.7.2 Localizing a drug’s area of activity
      • 14.7.3 Increasing absorption
    • 14.8 Endogenous compounds as drugs
      • 14.8.1 Neurotransmitters
      • 14.8.2 Natural hormones, peptides, and proteins as drugs
    • 14.9 Peptides and peptidomimetics in drug design
      • 14.9.1 Peptidomimetics
      • 14.9.2 Peptide drugs
    • 14.10 Oligonucleotides as drugs
    • Questions
    • Further Reading
    • List of Key Terms
  • 15 Getting the drug to market
    • 15.1 Preclinical and clinical trials
      • 15.1.1 Toxicity testing
      • 15.1.2 Drug metabolism studies
      • 15.1.3 Pharmacology, formulation, and stability tests
      • 15.1.4 Clinical trials
        • 15.1.4.1 Phase I studies
        • 15.1.4.2 Phase II studies
        • 15.1.4.3 Phase III studies
        • 15.1.4.4 Phase IV studies
        • 15.1.4.5 Ethical issues
    • 15.2 Patenting and regulatory affairs
      • 15.2.1 Patents
      • 15.2.2 Regulatory affairs
        • 15.2.2.1 The regulatory process
        • 15.2.2.2 Fast-tracking and orphan drugs
        • 15.2.2.3 Good laboratory, manufacturing, and clinical practice
        • 15.2.2.4 Cost-versus-benefit analysis
    • 15.3 Chemical and process development
      • 15.3.1 Chemical development
      • 15.3.2 Process development
      • 15.3.3 Choice of drug candidate
      • 15.3.4 Natural products
    • Questions
    • Further Reading
    • List of Key Terms
  • Case study 2 The design of ACE inhibitors
    • Further Reading
  • Case study 3 Artemisinin and related antimalarial drugs
    • CS3.1 Introduction
    • CS3.2 Artemisinin
    • CS3.3 Structure and synthesis of artemisinin
    • CS3.4 Structure–activity relationships
    • CS3.5 Mechanism of action
    • CS3.6 Drug design and development
    • Further Reading
    • List of Key Terms
  • Case study 4 The design of oxamniquine
    • CS4.1 Introduction
    • CS4.2 From lucanthone to oxamniquine
    • CS 4.3 Mechanism of action
    • CS4.4 Other agents
    • Further Reading
  • Case study 5 Fosmidomycin as an antimalarial agent
    • CS5.1 Introduction
    • CS5.2 The malarial parasite
    • CS5.3 The target for fosmidomycin: DOXP reductoisomerase
    • CS5.4 Fosmidomycin as a transition-state analogue
    • CS5.5 Binding interactions of fosmidomycin
    • CS5.6 Structure–activity relationships (SARs)
    • CS5.7 Properties of fosmidomycin
    • CS5.8 Analogues of fosmidomycin via an extension strategy
    • CS5.9 Prodrugs of fosmidomycin
    • Further Reading
• Part D Tools of the trade
  • 16 Combinatorial and parallel synthesis
    • 16.1 Combinatorial and parallel synthesis in medicinal chemistry projects
    • 16.2 Solid-phase techniques
      • 16.2.1 The solid support
      • 16.2.2 The anchor/linker
      • 16.2.3 Examples of solid-phase syntheses
    • 16.3 Planning and designing a compound library
      • 16.3.1 ‘Spider-like’ scaffolds
      • 16.3.2 Designing ‘drug-like’ molecules
      • 16.3.3 Synthesis of scaffolds
      • 16.3.4 Substituent variation
      • 16.3.5 Designing compound libraries for lead optimization
      • 16.3.6 Computer-designed libraries
    • 16.4 Testing for activity
      • 16.4.1 High-throughput screening
      • 16.4.2 Screening ‘on bead’ or ‘off bead’
    • 16.5 Parallel synthesis
      • 16.5.1 Solid-phase extraction
      • 16.5.2 The use of resins in solution phase organic synthesis (SPOS)
      • 16.5.3 Reagents attached to solid support: catch and release
      • 16.5.4 Microwave technology
      • 16.5.5 Microfluidics in parallel synthesis
    • 16.6 Combinatorial synthesis
      • 16.6.1 The mix and split method in combinatorial synthesis
      • 16.6.2 Structure determination of the active compound(s)
        • 16.6.2.1 Tagging
        • 16.6.2.2 Photolithography
      • 16.6.3 Dynamic combinatorial synthesis
    • Questions
    • Further Reading
    • List of Key Terms
  • 17 In silico drug design
    • 17.1 Molecular and quantum mechanics
      • 17.1.1 Molecular mechanics
      • 17.1.2 Quantum mechanics
      • 17.1.3 Choice of method
    • 17.2 Drawing chemical structures
    • 17.3 3D structures
    • 17.4 Energy minimization
    • 17.5 Viewing 3D molecules
    • 17.6 Molecular dimensions
    • 17.7 Molecular properties
      • 17.7.1 Partial charges
      • 17.7.2 Molecular electrostatic potentials
      • 17.7.3 Molecular orbitals
      • 17.7.4 Spectroscopic transitions
      • 17.7.5 The use of grids in measuring molecular properties
    • 17.8 Conformational analysis
      • 17.8.1 Local and global energy minima
      • 17.8.2 Molecular dynamics
      • 17.8.3 Stepwise bond rotation
      • 17.8.4 Monte Carlo and the Metropolis method
      • 17.8.5 Genetic and evolutionary algorithms
    • 17.9 Structure comparisons and overlays
    • 17.10 Identifying the active conformation
      • 17.10.1 X-ray crystallography
      • 17.10.2 Comparison of rigid and non-rigid ligands
    • 17.11 3D pharmacophore identification
      • 17.11.1 X-ray crystallography
      • 17.11.2 Structural comparison of active compounds
      • 17.11.3 Automatic identification of pharmacophores
    • 17.12 Docking procedures
      • 17.12.1 Manual docking
      • 17.12.2 Automatic docking
      • 17.12.3 Defining the molecular surface of a binding site
      • 17.12.4 Rigid docking by shape complementarity
      • 17.12.5 The use of grids in docking programs
      • 17.12.6 Rigid docking by matching hydrogen-bonding groups
      • 17.12.7 Rigid docking of flexible ligands: the FLOG program
      • 17.12.8 Docking of flexible ligands: anchor and grow programs
        • 17.12.8.1 Directed Dock and Dock 4.0
        • 17.12.8.2 FlexX
        • 17.12.8.3 The Hammerhead program
      • 17.12.9 Docking of flexible ligands: simulated annealing and genetic algorithms
    • 17.13 Automated screening of databases for lead compounds and drug design
    • 17.14 Protein mapping
      • 17.14.1 Constructing a model protein: homology modelling
      • 17.14.2 Constructing a binding site: hypothetical pseudoreceptors
    • 17.15 De novo drug design
      • 17.15.1 General principles of de novo drug design
      • 17.15.2 Automated de novo drug design
        • 17.15.2.1 LUDI
          • Stage 1: Identification of interaction sites
          • Stage 2: Fitting molecular fragments
          • Stage 3: Fragment bridging
        • 17.15.2.2 SPROUT
        • 17.15.2.3 LEGEND
        • 17.15.2.4 GROW, ALLEGROW, and SYNOPSIS
    • 17.16 Planning compound libraries
    • 17.17 Database handling
    • Questions
    • Further Reading
    • List of Key Terms
  • 18 Quantitative structure–activity relationships (QSAR)
    • 18.1 Graphs and equations
    • 18.2 Physicochemical properties
      • 18.2.1 Hydrophobicity
        • 18.2.1.1 The partition coefficient (P)
        • 18.2.1.2 The substituent hydrophobicity constant (π)
        • 18.2.1.3 P versus π
      • 18.2.2 Electronic effects
      • 18.2.3 Steric factors
        • 18.2.3.1 Taft’s steric factor (Es)
        • 18.2.3.2 Molar refractivity
        • 18.2.3.3 Verloop steric parameter
      • 18.2.4 Other physicochemical parameters
    • 18.3 Hansch equation
    • 18.4 The Craig plot
    • 18.5 The Topliss scheme
    • 18.6 Bio-isosteres
    • 18.7 The Free–Wilson approach
    • 18.8 Planning a QSAR study
    • 18.9 Case study: anti-allergic activity of a series of pyranenamines
    • 18.10 3D QSAR
      • 18.10.1 Defining steric and electrostatic fields
      • 18.10.2 Relating shape and electronic distribution to biological activity
      • 18.10.3 Advantages of CoMFA over traditional QSAR
      • 18.10.4 Potential problems of CoMFA
      • 18.10.5 Other 3D QSAR methods
      • 18.10.6 Case study: inhibitors of tubulin polymerization
    • Questions
    • Further Reading
    • List of Key Terms
  • Case study 6 Design of a thymidylate synthase inhibitor
    • Further Reading
    • List of Key Terms
• Part E Selected topics in medicinal chemistry
  • 19 Antibacterial agents
    • 19.1 History of antibacterial agents
    • 19.2 The bacterial cell
    • 19.3 Mechanisms of antibacterial action
    • 19.4 Antibacterial agents that act against cell metabolism (antimetabolites)
      • 19.4.1 Sulphonamides
        • 19.4.1.1 The history of sulphonamides
        • 19.4.1.2 Structure–activity relationships
        • 19.4.1.3 Sulphanilamide analogues
        • 19.4.1.4 Applications of sulphonamides
        • 19.4.1.5 Mechanism of action
      • 19.4.2 Examples of other antimetabolites
        • 19.4.2.1 Trimethoprim
        • 19.4.2.2 Sulphones
    • 19.5 Antibacterial agents that inhibit cell wall synthesis
      • 19.5.1 Penicillins
        • 19.5.1.1 History of penicillins
        • 19.5.1.2 Structure of benzylpenicillin and phenoxymethylpenicillin
        • 19.5.1.3 Properties of benzylpenicillin
        • 19.5.1.4 Mechanism of action for penicillin
          • Structure of the cell wall
          • The transpeptidase enzyme and its inhibition
        • 19.5.1.5 Resistance to penicillin
          • Physical barriers
          • Presence of β-lactamase enzymes
          • High levels of transpeptidase enzyme produced
          • Affinity of the transpeptidase enzyme to penicillin
          • Transport back across the outer membrane of Gram-negative bacteria
          • Mutations and genetic transfers
        • 19.5.1.6 Methods of synthesizing penicillin analogues
          • Fermentation
          • Semi-synthetic procedure
        • 19.5.1.7 Structure–activity relationships of penicillins
        • 19.5.1.8 Penicillin analogues
          • Acid sensitivity of penicillins
          • Acid-resistant penicillins
          • β-Lactamase-resistant penicillins
          • Broad-spectrum penicillins
          • Broad-spectrum penicillins: the aminopenicillins
          • Broad-spectrum penicillins: the carboxypenicillins
          • Broad-spectrum penicillins: the ureidopenicillins
        • 19.5.1.9 Synergism of penicillins with other drugs
      • 19.5.2 Cephalosporins
        • 19.5.2.1 Cephalosporin C
          • Discovery and structure of cephalosporin C
          • Properties of cephalosporin C
          • Structure–activity relationships of cephalosporin C
        • 19.5.2.2 Synthesis of cephalosporin analogues at position 7
        • 19.5.2.3 First-generation cephalosporins
        • 19.5.2.4 Second-generation cephalosporins
          • Cephamycins
          • Oximinocephalosporins
        • 19.5.2.5 Third-generation cephalosporins
        • 19.5.2.6 Fourth-generation cephalosporins
        • 19.5.2.7 Fifth-generation cephalosporins
        • 19.5.2.8 Resistance to cephalosporins
      • 19.5.3 Other β-lactam antibiotics
        • 19.5.3.1 Carbapenems
        • 19.5.3.2 Monobactams
      • 19.5.4 β-Lactamase inhibitors
        • 19.5.4.1 Clavulanic acid
        • 19.5.4.2 Penicillanic acid sulphone derivatives
        • 19.5.4.3 Olivanic acids
        • 19.5.4.4 β-Lactamase inhibitors lacking a β-lactam ring
      • 19.5.5 Other drugs that act on bacterial cell wall biosynthesis
        • 19.5.5.1 d-Cycloserine and bacitracin
        • 19.5.5.2 The glycopeptides: vancomycin and vancomycin analogues
    • 19.6 Antibacterial agents that act on the plasma membrane structure
      • 19.6.1 Valinomycin and gramicidin A
      • 19.6.2 Polymyxin B
      • 19.6.3 Killer nanotubes
      • 19.6.4 Cyclic lipopeptides
    • 19.7 Antibacterial agents that impair protein synthesis: translation
      • 19.7.1 Aminoglycosides
      • 19.7.2 Tetracyclines
      • 19.7.3 Chloramphenicol
      • 19.7.4 Macrolides
      • 19.7.5 Lincosamides
      • 19.7.6 Streptogramins
      • 19.7.7 Oxazolidinones
      • 19.7.8 Pleuromutilins
    • 19.8 Agents that act on nucleic acid transcription and replication
      • 19.8.1 Quinolones and fluoroquinolones
      • 19.8.2 Spiropyrimidinetriones
      • 19.8.3 Aminoacridines
      • 19.8.4 Rifamycins
      • 19.8.5 Nitroimidazoles and nitrofurantoin
      • 19.8.6 Inhibitors of bacterial RNA polymerase
    • 19.9 Miscellaneous agents
    • 19.10 Antibodies
    • 19.11 Drug resistance
      • 19.11.1 Drug resistance by mutation
      • 19.11.2 Drug resistance by genetic transfer
      • 19.11.3 Other factors affecting drug resistance
      • 19.11.4 The way ahead
    • Questions
    • Further Reading
    • List of Key Terms
  • 20 Antiviral agents
    • 20.1 Viruses and viral diseases
    • 20.2 Structure of viruses
    • 20.3 Life cycle of viruses
    • 20.4 Vaccination
    • 20.5 Antiviral drugs: general principles
    • 20.6 Antiviral drugs used against DNA viruses
      • 20.6.1 Inhibitors of viral DNA polymerase
      • 20.6.2 Inhibitors of the DNA terminase complex
      • 20.6.3 Kinase inhibitors
      • 20.6.4 Inhibitors of tubulin polymerization
      • 20.6.5 Antisense therapy
      • 20.6.6 Antiviral drugs acting against hepatitis B
    • 20.7 Antiviral drugs acting against RNA viruses: the human immunodeficiency virus (HIV)
      • 20.7.1 Structure and life cycle of HIV
      • 20.7.2 Antiviral therapy against HIV
      • 20.7.3 Inhibitors of viral reverse transcriptase
        • 20.7.3.1 Nucleoside reverse transcriptase inhibitors
        • 20.7.3.2 Non-nucleoside reverse transcriptase inhibitors
      • 20.7.4 Protease inhibitors
        • 20.7.4.1 The HIV protease enzyme
        • 20.7.4.2 Design of HIV protease inhibitors
        • 20.7.4.3 Saquinavir
        • 20.7.4.4 Ritonavir and lopinavir
        • 20.7.4.5 Indinavir
        • 20.7.4.6 Nelfinavir
        • 20.7.4.7 Palinavir
        • 20.7.4.8 Amprenavir and darunavir
        • 20.7.4.9 Atazanavir
        • 20.7.4.10 Tipranavir
        • 20.7.4.11 Alternative design strategies for antiviral drugs targeting the HIV protease enzyme
      • 20.7.5 Integrase inhibitors
      • 20.7.6 Cell entry inhibitors
        • 20.7.6.1 Fusion inhibitors targeting the viral gp41 glycoprotein
        • 20.7.6.2 Inhibitors of the viral glycoprotein gp120
        • 20.7.6.3 Inhibitors of the host cell CD4 protein
        • 20.7.6.4 Inhibitors of the host cell CCR5 chemokine receptor
    • 20.8 Antiviral drugs acting against RNA viruses: flu virus
      • 20.8.1 Structure and life cycle of the influenza virus
      • 20.8.2 Ion channel disrupters: adamantanes
      • 20.8.3 Neuraminidase inhibitors
        • 20.8.3.1 Structure and mechanism of neuraminidase
        • 20.8.3.2 Transition-state inhibitors: development of zanamivir (Relenza™)
        • 20.8.3.3 Transition-state inhibitors: 6-carboxamides
        • 20.8.3.4 Carbocyclic analogues: development of oseltamivir (Tamiflu™)
        • 20.8.3.5 Other ring systems
        • 20.8.3.6 Resistance studies
      • 20.8.4 Cap-dependent endonuclease inhibitors
    • 20.9 Antiviral drugs acting against RNA viruses: cold virus
    • 20.10 Antiviral drugs acting against RNA viruses: hepatitis C
      • 20.10.1 Inhibitors of HCV NS3-4A protease
        • 20.10.1.1 Introduction
        • 20.10.1.2 Design of boceprevir and telaprevir
        • 20.10.1.3 Second-generation protease inhibitors
      • 20.10.2 Inhibitors of HCV NS5B RNA-dependent RNA polymerase
      • 20.10.3 Inhibitors of HCV NS5A protein
        • 20.10.3.1 Symmetrical inhibitors
        • 20.10.3.2 Unsymmetrical inhibitors
      • 20.10.4 Other targets
    • 20.11 Broad-spectrum antiviral agents
      • 20.11.1 Agents acting against cytidine triphosphate synthetase
      • 20.11.2 Agents acting against S-adenosylhomocysteine hydrolase
      • 20.11.3 Ribavirin
      • 20.11.4 Interferons
      • 20.11.5 Antibodies and ribozymes
        • 20.11.5.1 Antibodies
        • 20.11.5.2 Ribozymes
    • 20.12 Bioterrorism and smallpox
    • Questions
    • Further Reading
    • List of Key Terms
  • 21 Anticancer agents
    • 21.1 Cancer: an introduction
      • 21.1.1 Definitions
      • 21.1.2 Causes of cancer
      • 21.1.3 Genetic faults leading to cancer: proto-oncogenes and oncogenes
        • 21.1.3.1 Activation of proto-oncogenes
        • 21.1.3.2 Inactivation of tumour suppression genes (anti-oncogenes)
        • 21.1.3.3 The consequences of genetic defects
      • 21.1.4 Abnormal signalling pathways
      • 21.1.5 Insensitivity to growth-inhibitory signals
      • 21.1.6 Abnormalities in cell cycle regulation
      • 21.1.7 Apoptosis and the p53 protein
      • 21.1.8 Telomeres
      • 21.1.9 Angiogenesis
      • 21.1.10 Tissue invasion and metastasis
      • 21.1.11 Treatment of cancer
      • 21.1.12 Resistance
    • 21.2 Drugs acting directly on nucleic acids
      • 21.2.1 Intercalating agents
      • 21.2.2 Non-intercalating agents that inhibit the action of topoisomerase enzymes on DNA
        • 21.2.2.1 Podophyllotoxins
        • 21.2.2.2 Camptothecins
      • 21.2.3 Alkylating and metallating agents
        • 21.2.3.1 Nitrogen mustards
        • 21.2.3.2 Cisplatin and cisplatin analogues: metallating agents
        • 21.2.3.3 CC 1065 analogues
        • 21.2.3.4 Ecteinascidins
        • 21.2.3.5 Other alkylating agents
      • 21.2.4 Chain cutters
    • 21.3 Drugs acting on enzymes: antimetabolites
      • 21.3.1 Dihydrofolate reductase inhibitors
      • 21.3.2 Inhibitors of thymidylate synthase
      • 21.3.3 Inhibitors of ribonucleotide reductase
      • 21.3.4 Inhibitors of adenosine deaminase
      • 21.3.5 Cytidine deaminase inhibitors
      • 21.3.6 Inhibitors of DNA polymerases
      • 21.3.7 Purine antagonists
      • 21.3.8 DNA methyltransferase inhibitors
    • 21.4 Hormone-based therapies
      • 21.4.1 Glucocorticoids, estrogens, progestins, and androgens
      • 21.4.2 Luteinizing hormone-releasing hormone receptor agonists and antagonists
      • 21.4.3 Anti-estrogens
      • 21.4.4 Anti-androgens
      • 21.4.5 Aromatase inhibitors
      • 21.4.6 Mitotane
      • 21.4.7 Somatostatin receptor agonists
    • 21.5 Drugs acting on structural proteins
      • 21.5.1 Agents that inhibit tubulin polymerization
      • 21.5.2 Agents that inhibit tubulin depolymerization
    • 21.6 Inhibitors of signalling pathways
      • 21.6.1 Inhibition of farnesyl transferase and the Ras protein
        • 21.6.1.1 Inhibition of farnesyl transferase
        • 21.6.1.2 Inhibition of KRAS
      • 21.6.2 Protein kinase inhibitors
      • 21.6.3 Receptor antagonists of the hedgehog signalling pathway
    • 21.7 Miscellaneous enzyme inhibitors
      • 21.7.1 Matrix metalloproteinase inhibitors
      • 21.7.2 Proteasome inhibitors
      • 21.7.3 Histone deacetylase inhibitors
      • 21.7.4 Inhibitors of poly ADP ribose polymerase
      • 21.7.5 Isocitrate dehydrogenase inhibitors
      • 21.7.6 Inhibitors for Enhancer of Zeste homologue 2
      • 21.7.7 Other enzyme targets
    • 21.8 Agents affecting pro-survival and pro-apoptotic proteins
    • 21.9 Agents affecting nuclear transport proteins
    • 21.10 Miscellaneous anticancer agents
      • 21.10.1 Synthetic agents
      • 21.10.2 Natural products
      • 21.10.3 Modulation of transcription factor–coactivator interactions
      • 21.10.4 PROTAC
    • 21.11 Photodynamic therapy
    • 21.12 Radionuclide therapy
    • 21.13 The role of biologics in anticancer therapy
    • Questions
    • Further Reading
    • List of Key Terms
  • 22 Protein kinase inhibitors as anticancer agents
    • 22.1 Introduction
      • 22.1.1 The active site of protein kinases
      • 22.1.2 Classification of protein kinase inhibitors
      • 22.1.3 Selectivity and resistance
    • 22.2 Kinase inhibitors of the epidermal growth factor receptor (EGFR)
    • 22.3 Kinase inhibitors of Abelson tyrosine kinase, c-KIT, PDGFR, and SRC
    • 22.4 Kinase inhibitors of c-KIT and PDGFR
    • 22.5 Inhibitors of cyclin-dependent kinases (CDKs)
    • 22.6 Kinase inhibitors of the MAPK signal transduction pathway
      • 22.6.1 BRAF inhibitors
      • 22.6.2 MEK inhibitors
    • 22.7 Kinase inhibitors of PI3K-PIP3 pathways
      • 22.7.1 Introduction
      • 22.7.2 Inhibitors of phosphoinositide 3-kinase
      • 22.7.3 Inhibitors of Bruton’s tyrosine kinase
    • 22.8 Kinase inhibitors of anaplastic lymphoma kinase (ALK)
    • 22.9 Kinase inhibitors of RET and KIF5B-RET
    • 22.10 Kinase inhibitors of Janus kinase
    • 22.11 Kinase inhibitors of vascular endothelial growth factor receptor (VEGFR)
    • 22.12 Kinase inhibitors of fibroblast growth factor receptor (FGFR)
    • 22.13 Kinase inhibitors of neurotrophic tropomyosin receptor tyrosine kinase (NTRK or TRK) and ROS1
    • 22.14 Kinase inhibitors of FMS-like tyrosine kinase 3 (FLT3)
    • 22.15 Kinase inhibitors of colony-stimulating factor-1 receptor (CSF-1R)
    • 22.16 Kinase inhibitors of the hepatocyte growth factor receptor (HGFR or c-MET)
    • 22.17 Multi-receptor tyrosine kinase inhibitors
    • 22.18 Kinase inhibition involving protein–protein binding interactions
    • 22.19 Kinase degradation induced by protein–protein binding interactions
    • 22.20 Summary
    • Questions
    • Further Reading
    • List of Key Terms
  • 23 Antibodies and other biologics
    • 23.1 The immune system
      • 23.1.1 Introduction
      • 23.1.2 Phagocytes
      • 23.1.3 B-cells, plasma cells, and antibody production
      • 23.1.4 T-cell lymphocytes
      • 23.1.5 The complement system
      • 23.1.6 Antibodies
    • 23.2 Antibody manufacture
    • 23.3 Monoclonal antibodies as anticancer agents
      • 23.3.1 Introduction
      • 23.3.2 Monoclonal antibodies targeting the HER family of receptors
      • 23.3.3 Antibodies targeting VEGF and VEGFR
      • 23.3.4 Antibodies targeting the RANK ligand
      • 23.3.5 Antibodies targeting the glycolipid GD2
      • 23.3.6 Antibodies targeting interleukins
      • 23.3.7 Antibodies targeting CD proteins in B-cells
        • 23.3.7.1 Antibodies targeting CD52
        • 23.3.7.2 Antibodies targeting CD20
        • 23.3.7.3 Antibodies targeting CD19
      • 23.3.8 Antibodies targeting CD proteins on plasma cells
        • 23.3.8.1 Antibodies targeting SLAMF7 (CD319)
        • 23.3.8.2 Antibodies targeting CD38
      • 23.3.9 Antibodies targeting the CCR4 receptor
      • 23.3.10 Monoclonal antibodies acting on immune checkpoints
        • 23.3.10.1 Introduction
        • 23.3.10.2 Antibodies targeting CTLA-4
        • 23.3.10.3 Antibodies targeting the programmed death receptor (PD-1)
        • 23.3.10.4 Antibodies targeting programmed death ligand 1
    • 23.4 Antibody–drug conjugates
      • 23.4.1 Introduction
      • 23.4.2 Antibody–drug conjugates targeting HER2
      • 23.4.3 Antibody–drug conjugates targeting trophoblast cell-surface antigen
      • 23.4.4 Antibody–drug conjugates targeting nectin 4
      • 23.4.5 Antibody–drug conjugates targeting B-cells
        • 23.4.5.1 Antibodies targeting CD19
        • 23.4.5.2 Antibodies targeting CD20
        • 23.4.5.3 Antibodies targeting CD22
        • 23.4.5.4 Antibodies targeting CD30
        • 23.4.5.5 Antibodies targeting CD33
        • 23.4.5.6 Antibodies targeting CD79
        • 23.4.5.7 Antibodies targeting CD142
    • 23.5 Antibody-directed enzyme prodrug therapy (ADEPT)
    • 23.6 Antibody-directed abzyme prodrug therapy (ADAPT)
    • 23.7 Gene-directed enzyme prodrug therapy (GDEPT)
    • 23.8 Other forms of anticancer therapy
      • 23.8.1 Gene therapy
      • 23.8.2 Antisense therapy
    • 23.9 Protein therapy
    • 23.10 Viral therapy
    • Questions
    • Further Reading
    • List of Key Terms
  • 24 Cholinergics, anticholinergics, and anticholinesterases
    • 24.1 The peripheral nervous system
    • 24.2 Motor nerves of the peripheral nervous system
      • 24.2.1 The somatic motor nervous system
      • 24.2.2 The autonomic motor nervous system
      • 24.2.3 The enteric system
      • 24.2.4 Defects in motor nerve transmission
    • 24.3 The cholinergic system
      • 24.3.1 The cholinergic signalling system
      • 24.3.2 Presynaptic control systems
      • 24.3.3 Co-transmitters
    • 24.4 Agonists at the cholinergic receptor
    • 24.5 Acetylcholine: structure, SAR, and receptor binding
    • 24.6 The instability of acetylcholine
    • 24.7 Design of acetylcholine analogues
      • 24.7.1 Steric shields
      • 24.7.2 Electronic effects
      • 24.7.3 Combining steric and electronic effects
    • 24.8 Clinical uses for cholinergic agonists
      • 24.8.1 Muscarinic agonists
      • 24.8.2 Nicotinic agonists
    • 24.9 Antagonists of the muscarinic cholinergic receptor
      • 24.9.1 Actions and uses of muscarinic antagonists
      • 24.9.2 Muscarinic antagonists
        • 24.9.2.1 Atropine and hyoscine
        • 24.9.2.2 Structural analogues of atropine and hyoscine
        • 24.9.2.3 Simplified analogues of atropine
        • 24.9.2.4 Quinuclidine muscarinic agents
        • 24.9.2.5 Other muscarinic antagonists
    • 24.10 Antagonists of the nicotinic cholinergic receptor
      • 24.10.1 Applications of nicotinic antagonists
      • 24.10.2 Nicotinic antagonists
        • 24.10.2.1 Curare and tubocurarine
        • 24.10.2.2 Decamethonium and suxamethonium
        • 24.10.2.3 Steroidal neuromuscular blocking agents
        • 24.10.2.4 Atracurium and mivacurium
        • 24.10.2.5 Other nicotinic antagonists
    • 24.11 Receptor structures
    • 24.12 Anticholinesterases and acetylcholinesterase
      • 24.12.1 Effect of anticholinesterases
      • 24.12.2 Structure of the acetylcholinesterase enzyme
      • 24.12.3 The active site of acetylcholinesterase
        • 24.12.3.1 Crucial amino acids within the active site
        • 24.12.3.2 Mechanism of hydrolysis
    • 24.13 Anticholinesterase drugs
      • 24.13.1 Carbamates
        • 24.13.1.1 Physostigmine
        • 24.13.1.2 Analogues of physostigmine
      • 24.13.2 Organophosphorus compounds
        • 24.13.2.1 Nerve agents
        • 24.13.2.2 Medicines
        • 24.13.2.3 Insecticides
    • 24.14 Pralidoxime: an organophosphate antidote
    • 24.15 Anticholinesterases as ‘smart drugs’
      • 24.15.1 Acetylcholinesterase inhibitors
      • 24.15.2 Dual-action agents acting on the acetylcholinesterase enzyme
      • 24.15.3 Multi-targeted agents acting on the acetylcholinesterase enzyme and the muscarinic M2 receptor
    • Questions
    • Further Reading
    • List of Key Terms
  • 25 Drugs acting on the adrenergic nervous system
    • 25.1 The adrenergic nervous system
      • 25.1.1 Peripheral nervous system
      • 25.1.2 Central nervous system
    • 25.2 Adrenergic receptors
      • 25.2.1 Types of adrenergic receptor
      • 25.2.2 Distribution of receptors
    • 25.3 Endogenous agonists for the adrenergic receptors
    • 25.4 Biosynthesis of catecholamines
    • 25.5 Metabolism of catecholamines
    • 25.6 Neurotransmission
      • 25.6.1 The neurotransmission process
      • 25.6.2 Co-transmitters
      • 25.6.3 Presynaptic receptors and control
    • 25.7 Drug targets
    • 25.8 The adrenergic binding site
    • 25.9 Structure–activity relationships (SARs)
      • 25.9.1 Important binding groups on catecholamines
      • 25.9.2 Selectivity for α- versus β-adrenoceptors
    • 25.10 Adrenergic agonists
      • 25.10.1 General adrenergic agonists
      • 25.10.2 α1-, α2-, β1-, and β3-agonists
      • 25.10.3 β2-agonists and the treatment of asthma
    • 25.11 Adrenergic receptor antagonists
      • 25.11.1 General α/β-blockers
      • 25.11.2 α-blockers
      • 25.11.3 β-blockers as cardiovascular drugs
        • 25.11.3.1 First-generation β-blockers
        • 25.11.3.2 Structure–activity relationships of aryloxypropanolamines
        • 25.11.3.3 Selective β1-blockers (second-generation β-blockers)
        • 25.11.3.4 Short-acting β-blockers
    • 25.12 Other drugs affecting adrenergic transmission
      • 25.12.1 Drugs that affect the biosynthesis of adrenergics
      • 25.12.2 Drugs inhibiting the uptake of noradrenaline into storage vesicles
      • 25.12.3 Release of noradrenaline from storage vesicles
      • 25.12.4 Reuptake inhibitors of noradrenaline into presynaptic neurons
      • 25.12.5 Inhibition of metabolic enzymes
    • Questions
    • Further Reading
    • List of Key Terms
  • 26 The opioid analgesics
    • 26.1 History of opium
    • 26.2 The active principle: morphine
      • 26.2.1 Isolation of morphine
      • 26.2.2 Structure and properties
    • 26.3 Structure–activity relationships
    • 26.4 The molecular target for morphine: opioid receptors
    • 26.5 Morphine: pharmacodynamics and pharmacokinetics
    • 26.6 Morphine analogues
      • 26.6.1 Variation of substituents
      • 26.6.2 Drug extension
      • 26.6.3 Simplification or drug dissection
        • 26.6.3.1 Removing ring E
        • 26.6.3.2 Removing ring D
        • 26.6.3.3 Removing rings C and D
        • 26.6.3.4 Removing rings B, C, and D
        • 26.6.3.5 Removing rings B, C, D, and E
      • 26.6.4 Rigidification
    • 26.7 Agonists and antagonists
    • 26.8 Endogenous opioid peptides and opioids
      • 26.8.1 Endogenous opioid peptides
      • 26.8.2 Analogues of enkephalins and δ-selective opioids
      • 26.8.3 Binding theories for enkephalins
      • 26.8.4 Inhibitors of peptidases
      • 26.8.5 Endogenous morphine
    • 26.9 The future
      • 26.9.1 The message–address concept
      • 26.9.2 Receptor dimers
      • 26.9.3 Selective opioid agonists versus multi-targeted opioids
      • 26.9.4 Peripheral-acting opioids
      • 26.9.5 Biased agonists
    • 26.10 Case study: design of nalfurafine
    • Questions
    • Further Reading
    • List of Key Terms
  • 27 Anti-ulcer agents
    • 27.1 Peptic ulcers
      • 27.1.1 Definition
      • 27.1.2 Causes
      • 27.1.3 Treatment
      • 27.1.4 Gastric acid release
    • 27.2 H2-Antagonists
      • 27.2.1 Histamine and histamine receptors
      • 27.2.2 Searching for a lead
        • 27.2.2.1 Histamine
        • 27.2.2.2 Nα-Guanylhistamine
      • 27.2.3 Developing the lead: a chelation bonding theory
      • 27.2.4 From partial agonist to antagonist: the development of burimamide
      • 27.2.5 Development of metiamide
      • 27.2.6 Development of cimetidine
      • 27.2.7 Cimetidine
        • 27.2.7.1 Biological activity
        • 27.2.7.2 Structure and activity
        • 27.2.7.3 Metabolism
      • 27.2.8 Further studies of cimetidine analogues
        • 27.2.8.1 Conformational isomers
        • 27.2.8.2 Desolvation
        • 27.2.8.3 Development of the nitroketeneaminal binding group
      • 27.2.9 Further H2-antagonists
        • 27.2.9.1 Ranitidine
        • 27.2.9.2 Famotidine and nizatidine
        • 27.2.9.3 H2-Antagonists with prolonged activity
      • 27.2.10 Comparison of H1- and H2-antagonists
      • 27.2.11 H2 Receptors and H2-antagonists
    • 27.3 Proton pump inhibitors (PPIs)
      • 27.3.1 Parietal cells and the proton pump
      • 27.3.2 PPIs
      • 27.3.3 Mechanism of inhibition
      • 27.3.4 Metabolism of PPIs
      • 27.3.5 Design of omeprazole and esomeprazole
      • 27.3.6 Other PPIs
    • 27.4 Helicobacter pylori and the use of antibacterial agents
      • 27.4.1 Discovery of Helicobacter pylori
      • 27.4.2 Treatment
    • 27.5 Traditional and herbal medicines
    • Questions
    • Further Reading
    • List of Key Terms
  • 28 Cardiovascular drugs
    • 28.1 Introduction
    • 28.2 The cardiovascular system
    • 28.3 Antihypertensives affecting the activity of the RAAS system
      • 28.3.1 Introduction
      • 28.3.2 Renin inhibitors
      • 28.3.3 ACE inhibitors
      • 28.3.4 Angiotensin receptor antagonists
      • 28.3.5 Mineralocorticoid receptor antagonists
      • 28.3.6 Dual-action agents
    • 28.4 Endothelin receptor antagonists as antihypertensive agents
      • 28.4.1 Endothelins and endothelin receptors
      • 28.4.2 Endothelin antagonists
      • 28.4.3 Dual-action agents
    • 28.5 Vasodilators
      • 28.5.1 Modulators of soluble guanylate cyclase
      • 28.5.2 Phosphodiesterase type 5 inhibitors
      • 28.5.3 Neprilysin inhibitors
      • 28.5.4 Prostacyclin agonists
      • 28.5.5 Miscellaneous vasodilators
    • 28.6 Calcium entry blockers
      • 28.6.1 Introduction
      • 28.6.2 Dihydropyridines
      • 28.6.3 Phenylalkylamines
      • 28.6.4 Benzothiazepines
    • 28.7 Funny ion channel inhibitors
    • 28.8 Lipid-regulating agents
      • 28.8.1 Statins
      • 28.8.2 Fibrates
      • 28.8.3 Dual- and pan-PPAR agonists
      • 28.8.4 Antisense drugs
      • 28.8.5 Inhibitors of transfer proteins
      • 28.8.6 Antibodies as lipid-lowering agents
      • 28.8.7 ATP citrate lyase inhibitors
    • 28.9 Antithrombotic agents
      • 28.9.1 Anticoagulants
        • 28.9.1.1 Introduction
        • 28.9.1.2 Direct thrombin inhibitors
        • 28.9.1.3 Factor Xa inhibitors
      • 28.9.2 Antiplatelet agents
        • 28.9.2.1 Introduction
        • 28.9.2.2 PAR-1 antagonists
        • 28.9.2.3 P2Y12-Antagonists
        • 28.9.2.4 GpIIb/IIIa antagonists
      • 28.9.3 Fibrinolytic drugs
    • Questions
    • Further Reading
    • List of Key Terms
  • Case Study 7 Steroidal anti-inflammatory agents
    • CS7.1 Introduction to steroids
    • CS7.2 Orally active analogues of cortisol
    • CS7.3 Topical glucocorticoids as anti-inflammatory agents
      • CS7.3.1 Cortisol analogues
      • CS7.3.2 21-Deoxysteroids
      • CS7.3.3 11-Ketosteroids
      • CS7.3.4 Analogues with modified C-17 side chains
      • CS7.3.5 Glucocorticoids used in asthma treatment
      • CS7.3.6 Glucocorticoids used in ophthalmology
      • CS7.3.7 Sustained release of topical anti-inflammatory agents
    • List of Key Terms
  • Case Study 8 Current research into antidepressant agents
    • CS8.1 Introduction
    • CS8.2 The monoamine hypothesis
    • CS8.3 Current antidepressant agents
    • CS8.4 Current areas of research
    • CS8.5 Antagonists for the 5-HT7 receptor
    • Further Reading
    • List of Key Terms
  • Case Study 9 The design and development of aliskiren
    • CS9.1 Introduction
    • CS9.2 Reaction catalysed by renin
    • CS9.3 From lead compound to peptide inhibitors
    • CS9.4 Peptidomimetic strategies
    • CS9.5 Design of non-peptide inhibitors
    • CS9.6 Optimization of the structure
    • Further Reading
    • List of Key Terms
  • Case Study 10 Factor Xa inhibitors
    • CS10.1 Introduction
    • CS10.2 The target
    • CS10.3 General strategies in the design of factor Xa inhibitors
    • CS10.4 Apixaban: from hit structure to lead compound
    • CS10.5 Apixaban: from lead compound to final structure
    • CS10.6 The development of rivaroxaban
    • CS10.7 The development of edoxaban
    • Further Reading
  • Case Study 11 Reversible inhibitors of HCV NS3-4A protease
    • CS11.1 Introduction
    • CS11.2 Identification of a lead compound
    • CS11.3 Modifications of the lead compound
    • CS11.4 From hexapeptide to tripeptide
    • CS11.5 From tripeptide to macrocycle (BILN-2061)
    • CS11.6 From BILN-2061 to simeprevir
    • Further Reading
• Appendix 1 Essential amino acids
• Appendix 2 The standard genetic code
• Appendix 3 Statistical data for QSAR
• Appendix 4 The action of nerves
• Appendix 5 Microorganisms
• Appendix 6 Drugs and their trade names
• Appendix 7 Trade name (drug name)
• Appendix 8 Potential hydrogen bond donors (HBDs) and hydrogen bond acceptors (HBAs) in common functional groups
• Appendix 9 Using the Protein Data Bank
  • List of Key Terms
• Glossary
• General Further Reading
• Index
• List of Illustrations
• List of Tables
• Images
  • 1 Drugs and drug targets: an overview
  • 2 Protein structure and function
  • 3 Enzymes: structure and function
  • 4 Receptors: structure and function
  • 5 Receptors and signal transduction
  • 6 Nucleic acids: structure and function
  • 7 Enzymes as drug targets
  • 8 Receptors as drug targets
  • 9 Nucleic acids as drug targets
  • 10 Miscellaneous drug targets
  • 11 Pharmacokinetics and related topics
  • Case study 1 Statins
  • 12 Drug discovery: finding a lead
  • 13 Drug design: optimizing target interactions
  • 14 Drug design: optimizing access to the target
  • 15 Getting the drug to market
  • Case study 2 The design of ACE inhibitors
  • Case study 3 Artemisinin and related antimalarial drugs
  • Case study 4 The design of oxamniquine
  • Case study 5 Fosmidomycin as an antimalarial agent
  • 16 Combinatorial and parallel synthesis
  • 17 In silico drug design
  • 18 Quantitative structure–activity relationships (QSAR)
  • Case study 6 Design of a thymidylate synthase inhibitor
  • 19 Antibacterial agents
  • 20 Antiviral agents
  • 21 Anticancer agents
  • 22 Protein kinase inhibitors as anticancer agents
  • 23 Antibodies and other biologics
  • 24 Cholinergics, anticholinergics, and anticholinesterases
  • 25 Drugs acting on the adrenergic nervous system
  • 26 The opioid analgesics
  • 27 Anti-ulcer agents
  • 28 Cardiovascular drugs
  • Case Study 7 Steroidal anti-inflammatory agents
  • Case Study 8 Current research into antidepressant agents
  • Case Study 9 The design and development of aliskiren
  • Case Study 10 Factor Xa inhibitors
  • Case Study 11 Reversible inhibitors of HCV NS3-4A protease
  • Appendix 1

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