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 trans

lgrsnf/An Introduction to Medicinal Chemistry, 7e (Jun 15, 2023)_(0198866666)_(Oxford University Press).pdf

zlib/Chemistry/Chemistry - General & Miscellaneous/Graham Patrick/an introduction to Medicinal Chemistry_27848628.pdf

Patrick, Graham L.

IRL Press at Oxford University Press

Oxford Institute for Energy Studies

German Historical Institute London

United Kingdom and Ireland, United Kingdom

Seventh edition, New York, NY, 2023

Seventh edition, Oxford, 2023

S.l, 2023

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 (RelenzaTM)
20.8.3.3 Transition-state inhibitors: 6-carboxamides
20.8.3.4 Carbocyclic analogues: development of oseltamivir (TamifluTM)
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 tra

2024-02-23