This textbook is an overview of the subject of medicinal chemistry within the context of drug design and
discovery. Both of us were trained as synthetic organic chemists and had our “first” careers in medicinal
chemistry departments at major pharmaceutical companies. Upon moving into academia, we both took on
teaching a one-semester class in medicinal chemistry. Anyone who has taught this type of course quickly
realizes the difficulty in bringing together the many aspects that comprise this subject, such as organic
chemistry, pharmacology, and biochemistry, as well as introducing therapeutic areas in medicinal chemistry in
just one semester. After teaching this course for many years using various review articles as text, as well as
material written ourselves, we decided to write this textbook. We have tried to write a text that includes the
historical background of drug discovery but emphasizes modern practices in design, discovery, and
development. We focus on drug targets and how current knowledge of these targets drives medicinal chemistry
and drug discovery. While it is not possible to cover all therapeutic areas in a one-semester text, selected areas
and classes of drugs are also included. Overall, we intend for this text to meet the need for a modern, onesemester textbook that ties together the many different aspects of medicinal chemistry as it is currently
practiced.
The target audience is primarily upper-level undergraduate students and beginning graduate students in
organic chemistry and medicinal chemistry. Other students who might find the text useful include pharmacy
students and anyone planning to pursue a career in the drug discovery field. In addition to science majors, we
have had students from fields as diverse as finance, engineering, and biomedical ethics take our courses, all
with a common interest in learning about drug discovery. The book should also be useful for professional
scientists, such as chemists, biologists, and patent professionals, who are just entering the drug discovery field
and may not have had direct experience with medicinal chemistry. It is expected that those using this textbook
have a basic knowledge of organic chemistry as well as basic biology.
To present this broad subject in a way that is logical and covers essential topics in a one-semester format,
our approach is to divide the text into three sections. PART I, Drug Discovery and Development: the first five
chapters cover historical background in drug discovery, as well as the modern drug discovery and development
process, with an emphasis on medicinal chemistry strategies used in various phases. These chapters give the
essential background of hit and lead discovery, modifications driven by knowledge of both target and
pharmacophore structure, common medicinal chemistry strategies, and the central importance of
pharmacokinetics. They provide the background that subsequent chapters build upon. PART II, Classes of
Drug Targets: Chapters 6-9 focus on the major drug targets, namely, their structure and function and how
medicinal chemists approach each. Examples of specific drugs developed for each type of target are included.
Targets include receptors and ion channels, enzymes, protein-protein and lipid interactions, and nucleic acids.
Each of those is broken down into more specific classes of important drug targets. These chapters can be
covered in any order but reference topics in Chapters 1-5. PART III, Selected Therapeutic Areas: the final
chapters, 10-13, are devoted to selected important therapeutic areas. While there are many more chapters that
could have been written on additional areas of interest, these topics were selected as examples that tie together
components introduced in the earlier chapters and represent both historically important agents and future
opportunities. Those topics included are anti-cancer, antibacterial, and antiviral drugs and drugs acting on the
central nervous system. A subset of Chapter 13 is devoted to drugs of abuse, informed by student interest on
this topic. Any of these last chapters on specific therapeutic areas can be considered optional or used
independently, but they also rely on the material covered in Chapters 1-9.
Author(s): Norma Dunlap, Donna Huryn
Publisher: Garland Science, Taylor & Francis Group
Year: 2018
Language: English
City: New York
Tags: chemotherapy, pharmaceutical chemistry
CONTENTS
PART I DRUG DISCOVERY AND DEVELOPMENT
Chapter 1 Historical perspective and overview of drug discovery
Historical Perspective of the Practice of Medicinal Chemistry
1.1 Many medicines were originally isolated from plants
1.2 Semisynthetic drugs are prepared from natural products
Overview of the Practice of Medicinal Chemistry in the Modern Era
1.3 Identification of complex structures began in the early 1900s
1.4 Advances in total synthesis allow access to natural products and analogs
1.5 Medicinal chemistry currently is based on the molecular causes of disease
Summary
Case Study 1 Discovery of Artemisinin
Case Study 2 Discovery Of Ingenol Mebutate
Review Questions
Application Questions
Further Reading
Chapter 2 Drug discovery: hit and lead identification
Overview of Drug Discovery Process
Identification of Hits and Leads
2.1 Various types of assays are used in screening for hit and lead identification
Sources of Hits and Leads in Drug Discovery: Compounds with Known Bioactivity
2.2 Plant-based sources are the starting points for many drugs
2.3 Microbes and higher animals may be sources for hits, leads, and drugs
2.4 Hits and leads are often based on natural ligands
2.5 Compounds with reported bioactivity are important sources of hits and leads
2.6 Clinical observations may uncover unexpected activities of known bioactive compounds
Sources of Hits and Leads in Drug Discovery: Synthetic Libraries
2.7 Legacy libraries contain compounds from prior discovery campaigns
2.8 Combinatorial libraries are sets of closely related analogs that can be prepared by parallel or
split-pool synthesis
2.9 Diversity-oriented synthesis is another strategy used in designing synthetic libraries
Methods for Screening Compound Libraries
2.10 High-throughput screening assays large numbers of compounds by a variety of different
techniques
2.11 Fragment-based screening detects direct binding to a protein target
2.12 Virtual libraries can be screened by computational algorithms
Identification of High-Quality Hits from Screening
2.13 False positives and nuisance compounds need to be eliminated from primary hit lists
2.14 Hits identified in screening campaigns need to be prioritized
Summary
Case Study 1 Example of Fragment-Based Screening
Case Study 2 Example of Virtual Screening
Review Questions
Application Questions
Further Reading
Chapter 3 Lead optimization: drug-target interactions and the pharmacophoreOptimization of Drug-Target Interactions
3.1 Optimization of binding depends on specific molecular interactions
3.2 Specific interactions contribute to the overall binding of drugs to their targets
Tools Used to Develop Structure-Activity Relationships
3.3 Historical methods for quantifying structure-activity relationships were based on
physicochemical parameters
3.4 Ligandand structure-based drug design are modern strategies that rely on knowledge of the
pharmacophore
3.5 Pharmacophore models are widely used in ligand-based drug design
3.6 Structure-based drug design is based on the structure of the drug target
Summary
Case Study 1 Example of The Use of A Pharmacophore Model in Virtual Screening
Case Study 2 Example of the Use of Structure-Based Drug Design
Review Questions
Application Questions
Further Reading
Chapter 4 Lead optimization: properties optimized and medicinal chemistry strategies
Properties Evaluated During Lead Optimization
4.1 Biological activity is optimized as a component of the lead optimization process
4.2 Physical and pharmaceutical properties are optimized in parallel with biological properties
Optimization of Lead Properties
4.3 Rules and metrics have been developed to aid the lead optimization process
4.4 Lipophilicity is optimized so that a drug can reach its target
4.5 Leads need to be optimized for solubility in aqueous media
4.6 Optimization of metabolic stability is a necessary component of lead optimization
4.7 Targeting strategies and the use of prodrugs improve drug properties
Medicinal Chemistry Strategies Applied During Lead Optimization
4.8 Increasing steric bulk affects binding, lipophilicity, and metabolic stability
4.9 Bioisosteres are used as substitutions for specific functional groups
4.10 Scaffold hopping is a subset of bioisosterism
4.11 Incorporation of fluorine may affect potency and pharmaceutical properties
4.12 Transition-state mimetics are common features of enzyme inhibitors
4.13 Conformational constraints can be used to improve binding to the drug target
4.14 Privileged structures are structural templates found in multiple drugs
Summary
Case Study 1 Lead Optimization of Losartan
Case Study 2 Discovery and Strategies Used in Development of Cimetidine to Treat Gastric
Ulcers
Review Questions
Further Reading
Chapter 5 The process of developing a drug from an optimized lead
Patenting and Drug Discovery and Development
5.1 Three versions of patents are commonly filed during the drug discovery process
Process Chemistry Research
Characterization of Pharmacokinetic Properties of Leads
5.2 Absorption is one determinant of how much drug reaches its biological target
5.3 Distribution determines which tissues accumulate drugs
5.4 Metabolism and elimination are the body’s method for removing drugs
Drug Toxicity Determination
5.5 Indications of toxicity are identified early in the drug discovery stage by in vitro assays
5.6 Toxicity testing is done with in vivo assays in multiple animal species5.7 Formulation of the final drug product
Clinical Trials in Humans
Summary
Case Study 1 Discovery of Fluoxetine
Case Study 2 Development of Rivaroxaban (Xarelto)
Review Questions
Application Questions
Further Reading
PART II CLASSES OF DRUG TARGETS
Chapter 6 Receptors, ion channels, and transporters as drug targets
G Protein-Coupled Receptors as Drug Targets
6.1 GPCRs are defined by structural features
6.2 Ligands bind to GPCRs and may activate or inactivate a receptor
6.3 Drug activity is classified by examining biological response as compared to dose
6.4 Theories have been developed to explain how drugs binding at the same receptor site may have
different types of activity
6.5 Drugs acting at GPCRs include drugs to treat allergy, cardiovascular disease, asthma, and
ulcers
Ion Channels (Ionotropic Receptors) As Drug Targets
6.6 Ligand-gated ion channels open or close in response to binding of a drug or natural ligand
6.7 Neuromuscular blockers, sedatives, and anti-nausea agents are examples of drugs acting at
LGICs
6.8 Voltage-gated ion channels open or close in response to changes in membrane potential
6.9 Blockers of sodium, calcium and potassium VGICs include local anesthetics, anticonvulsants,
and anti-arrhythmia drugs
Nuclear Receptors As Drug Targets
6.10 Drugs that target nuclear receptors are used to treat cancer, inflammation, and diabetes and to
regulate the physiological effects of sex hormones
Transporters As Drug Targets
6.11 Drugs acting at transporters treat a wide array of neuropsychiatric disorders, hypertension,
and diabetes
Summary
Case Study 1 Discovery of Ramelteon
Case Study 2 Discovery of Rosiglitazone
Review Questions
Application Questions
Further Reading
General
G protein-coupled receptors
Ion channels
Nuclear receptors
Transporters
Ramelteon
Rosiglitazone
Web sites
Chapter 7 Enzymes as drug targets
Effect of Small-Molecule Modulators on Enzymes
7.1 Modulators are classified by how they interact with an enzyme
7.2 Effects on enzyme kinetics are used to characterize the mechanism of small-molecule
modulators7.3 Enzymes are frequent targets of drug action
Kinases and Kinase Inhibitor Drugs
7.4 Kinase inhibitors work through multiple binding modes and are effective anti-cancer drugs and
anti-inflammatory agents
Proteases and Protease Inhibitors
7.5 Protease inhibitors are designed on the basis of the enzyme’s mechanism of action and are
useful for treating HIV and bacterial infections as well as cardiovascular disease
Polymerases and Polymerase Inhibitors
7.6 Inhibitors of polymerases can mimic the substrate or bind at an allosteric site
Esterases, Phosphodiesterases, and Their Inhibitors
7.7 Inhibitors of phosphodiesterases treat cardiovascular disease, respiratory disease, and erectile
dysfunction
Oxidoreductases, Cyclooxygenases, and Inhibitors
7.8 Inhibitors of HMG-CoA reductase are used to lower cholesterol levels
7.9 Inhibitors of cyclooxygenase are effective anti-inflammatory drugs
Summary
Case Study 1 Discovery of the Proteint Tyrosine Kinase Inhibitor Imatinib
Case Study 2 Development of Enalapril
Review Questions
Application Questions
Further Reading
Chapter 8 Protein-protein and lipid structure interactions as drug targets
Protein-Protein Interactions As Drug Targets
8.1 One strategy to prevent binding between two proteins is to mimic one of the protein partners
8.2 Modulators of protein-protein interactions may change the equilibrium of a multiprotein
complex, and examples of such are valuable anti-cancer agents
8.3 Modulators of protein-protein interactions can reduce levels of misactive proteins, and
examples are useful to treat rare diseases
Lipids of Cell Membranes as Drug Targets
8.4 Drugs acting at lipids in membranes act as anti-infective agents
Summary
Case Study 1 Discovery of Taxol
Case Study 2 Discovery of Maraviroc
Review Questions
Application Questions
Further Reading
Protein-protein interactions
Tubulin modulators
RGD mimetics
Transthyretin
Taxol
Maraviroc
Chapter 9 DNA and RNA as drug targets
DNA as a Drug Target
9.1 Intercalation is one of the main mechanisms by which small molecules interact with DNA
9.2 Drugs may bind in the minor groove of DNA through reversible noncovalent interactions
9.3 Drugs that interact with DNA by irreversible mechanisms are anti-cancer agents
9.4 Compounds that cleave DNA after binding and generating free radicals are powerful drugs
used to treat cancer
RNA as a Drug Target9.5 Compounds targeting bacterial ribosomal RNA inhibit protein synthesis and are useful antiinfective agents
9.6 Antisense therapies targeting RNA are effective in treating rare diseases and infections
Summary
Case Study 1 Doxorubicin And Analogs
Case Study 2 Discovery of Mipomersen
Review Questions
Application Questions
Further Reading
DNA drugs
RNA drugs
Actinomycins
Mipomersen
PART III SELECTED THERAPEUTIC AREAS
Chapter 10 Anti-cancer drugs
Drugs Targeting DNA Replication and Mitosis
10.1 Drugs may target DNA and DNA processing enzymes such as polymerase and topoisomerase
10.2 Drugs may target biosynthesis of DNA building blocks
10.3 Drugs may target structural proteins involved in cell division
10.4 Effects of antitumor compounds may be optimized by targeting delivery systems
Drugs Targeting Oncogenes and Signaling Pathways
10.5 Kinase inhibitors target mutant or overexpressed kinases found in cancer cells
Inhibition of Angiogenesis
Drugs Targeting the Ubiquitin-Proteasome Pathway
Drugs Targeting Epigenetic Processes
10.6 Nucleosides with modified bases can act as DNA methyltransferase inhibitors
10.7 Histone deacetylase inhibitors bind to zinc in the enzyme’s active site
Drugs Targeting Hormone-Dependent Tumors
Summary
Case Study 1 Discovery of Vorinostat
Case Study 2 Vismodegib: Inhibitor of Hedgehog Signaling Pathway
Review Questions
Application Questions
Further Reading
Chapter 11 Antiviral and antifungal agents
Antiviral Agents: Common Viral Structures, Replication Process, and Impact
Antiviral Drug Discovery
Antiviral Drugs Targeting Viral Life Cycle
11.1 Drugs may target viral attachment or entry
11.2 Drugs may target uncoating of viral particles
11.3 Many antiviral drugs inhibit transcription by targeting the active site of polymerases
11.4 Prodrugs improve the properties and effectiveness of nucleosides
11.5 Some HIV drugs that target reverse transcriptase bind at allosteric sites
11.6 Viral protease inhibitors have been developed by use of structure-based drug design
11.7 Inhibitors of the hepatitis C virus NS5A replication complex exhibit antiviral activity
11.8 Drugs to treat retroviruses may target the viral integrase
11.9 Influenza drugs target viral budding
Antifungal Agents: Common Fungal Structures, Replication Process, and Impact
Antifungal Drug Discovery
Drugs Targeting Fungi11.10 Polyene drugs target the fungal cell membrane
11.11 Azoles and allylamines inhibit ergosterol biosynthesis
11.12 Some antifungal drugs inhibit cell replication
11.13 Echinocandins inhibit fungal cell-wall synthesis
Summary
Case Study 1 Discovery of Daclatasvir
Case Study 2 Discovery of Rilpivirine
Review Questions
Application Questions
Further Reading
HIV/HCV
Acyclic nucleosides and phosphonates
Neuraminidase inhibitors
Antifungal agents
Chapter 12 Antibacterial and antiparasitic drugs
Antibacterial Agents: Bacterial Structure, Points of Drug Interaction, And Impact
Antibacterial Drug Discovery
Bacterial Cell-Wall Synthesis Inhibitors
12.1 -Lactam antibacterial compounds are the largest class of cell-wall synthesis inhibitors
12.2 Glycopeptide antibacterial agents inhibit cell-wall synthesis by a different mechanism than βlactams
Bacterial Protein Synthesis Inhibitors
12.3 Aminoglycosides, tetracyclines, and erythromycins are protein synthesis inhibitors based on
natural products
12.4 Oxazolidinones are inhibitors of protein synthesis
Drugs Targeting Bacterial DNA Replication
12.5 Quinolone antibacterial agents inhibit DNA gyrase
12.6 Sulfonamide antibacterial compounds inhibit folic acid biosynthesis
Drugs Affecting Bacterial Cell-Membrane Permeability
Antiparasitic Drugs: Common Parasite Features, Infectious Process, and Impact
Antiparasitic Drug Discovery
12.7 Current drugs used to treat malaria are derivatives of natural products
12.8 There are few effective treatments for trypanosomal diseases
12.9 Drugs that treat helminthic diseases are used in both veterinary and human medicine
Summary
Case Study 1 Discovery Of Linezolid
Case Study 2 Sq109 For Multi-Drug-Resistant Tuberculosis
Review Questions
Application Questions
Further Reading
Chapter 13 Drugs acting on the central nervous system
Drugs Targeting Anxiety and Depression
13.1 Positive allosteric modulators at the GABAA
receptor are sedatives and anticonvulsants
13.2 Drugs that increase monoamine neurotransmitter levels or act as partial agonists at
neurotransmitter receptors are antidepressants
Drugs Targeting Psychosis
13.3 Typical antipsychotics act as dopamine receptor antagonists
13.4 The mechanism of atypical antipsychotics involves dopamine receptor antagonism combined
with serotonin receptor antagonism
13.5 Drugs targeting glutamate and phosphodiesterase 10A have potential as antipsychotics
Drugs Targeting Pain13.6 Drugs used to treat pain include opiates and nonsteroidal antiinflammatory drugs as well as
antidepressants
13.7 Novel approaches to pain treatment include selective ion channel blockers
13.8 Selective serotonin agonists are used to treat migraine
Drugs Targeting Neurodegeneration
13.9 Approved drugs to treat Alzheimer’s disease affect acetylcholine or glutamate levels
13.10 Recent approaches to modifying the course of Alzheimer’s disease have focused on
decreasing production of amyloid plaques
13.11 Drugs developed to treat Parkinson’s disease are based on increasing dopamine levels
Drugs of Abuse
13.12 Stimulants include both legal and illegal drugs
13.13 Hallucinogens include serotonin receptor agonists and N-methyl-d-aspartate antagonists
13.14 Cannabinoids have potential medical uses
Summary
Case Study 1 Development of Vilazodone
Case Study 2 Discovery of Donepezil
Review Questions
Application Questions
Further Reading
Answers to End of Chapter Review Questions
Glossary
Index
