The Organic Chemistry of Drug Design and Drug Action

The Organic Chemistry of Drug Design and Drug Action, 3rd Edition

The Organic Chemistry of Drug Design and Drug Action, 3rd Edition,Richard B. Silverman,Mark W. Holladay,ISBN9780123820303


Academic Press




The Organic Chemistry of Drug Design and Drug Action, Third Edition, represents a unique approach to medicinal chemistry based on physical organic chemical principles and reaction mechanisms that rationalize drug action, which allows the reader to extrapolate those core principles and mechanisms to many related classes of drug molecules.

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Key Features

New to this edition:

  • Updates to all chapters, including new examples and references
  • Chapter 1 (Introduction): Completely rewritten and expanded as an overview of topics discussed in detail throughout the book
  • Chapter 2 (Lead Discovery and Lead Modification): Sections on sources of compounds for screening including library collections, virtual screening, and computational methods, as well as hit-to-lead and scaffold hopping; expanded sections on sources of lead compounds, fragment-based lead discovery, and molecular graphics; and deemphasized solid-phase synthesis and combinatorial chemistry
  • Chapter 3 (Receptors): Drug-receptor interactions, cation-p and halogen bonding; atropisomers; case history of the insomnia drug suvorexant
  • Chapter 4 (Enzymes): Expanded sections on enzyme catalysis in drug discovery and enzyme synthesis
  • Chapter 5 (Enzyme Inhibition and Inactivation): New case histories:
    • for competitive inhibition, the epidermal growth factor receptor tyrosine kinase inhibitor, erlotinib and Abelson kinase inhibitor, imatinib
    • for transition state analogue inhibition, the purine nucleoside phosphorylase inhibitors, forodesine and DADMe-ImmH, as well as the mechanism of the multisubstrate analog inhibitor isoniazid
    • for slow, tight-binding inhibition, the dipeptidyl peptidase-4 inhibitor, saxagliptin
  • Chapter 7 (Drug Resistance and Drug Synergism): This new chapter includes topics taken from two chapters in the previous edition, with many new examples
  • Chapter 8 (Drug Metabolism): Discussions of toxicophores and reactive metabolites
  • Chapter 9 (Prodrugs and Drug Delivery Systems): Discussion of antibody-drug conjugates


The Organic Chemistry of Drug Design and Drug Action, Third Edition, represents a unique approach to medicinal chemistry based on physical organic chemical principles and reaction mechanisms that rationalize drug action, which allows the reader to extrapolate those core principles and mechanisms to many related classes of drug molecules. This new edition reflects significant changes in the process of drug design over the last decade. It preserves the successful approach of the previous editions while including significant changes in format and coverage.


Undergraduate and graduate students in chemistry studying medicinal chemistry or pharmaceutical chemistry; research chemists and biochemists working in pharmaceutical and biotechnology industries.

Richard B. Silverman

Ph.D Organic Chemistry

Professor Richard B. Silverman received his B.S. degree in chemistry from The Pennsylvania State University in 1968 and his Ph.D. degree in organic chemistry from Harvard University in 1974 (with time off for a two-year military obligation from 1969-1971). After two years as a NIH postdoctoral fellow in the laboratory of the late Professor Robert Abeles in the Graduate Department of Biochemistry at Brandeis University, he joined the chemistry faculty at Northwestern University. In 1986, he became Professor of Chemistry and Professor of Biochemistry, Molecular Biology, and Cell Biology. In 2001, he became the Charles Deering McCormick Professor of Teaching Excellence for three years, and since 2004 he has been the John Evans Professor of Chemistry. His research can be summarized as investigations of the molecular mechanisms of action, rational design, and syntheses of potential medicinal agents acting on enzymes and receptors. His awards include DuPont Young Faculty Fellow (1976), Alfred P. Sloan Research Fellow (1981-1985), NIH Research Career Development Award (1982-1987), Fellow of the American Institute of Chemists (1985), Fellow of the American Association for the Advancement of Science (1990), Arthur C. Cope Senior Scholar Award of the American Chemical Society (2003), Alumni Fellow Award from Pennsylvania State University (2008), Medicinal Chemistry Hall of Fame of the American Chemical Society (2009), the Perkin Medal from the Society of Chemical Industry (2009), the Hall of Fame of Central High School of Philadelphia (2011), the E.B. Hershberg Award for Important Discoveries in Medicinally Active Substances from the American Chemical Society (2011), Fellow of the American Chemical Society (2011), Sato Memorial International Award of the Pharmaceutical Society of Japan (2012), Roland T. Lakey Award of Wayne State University (2013), BMS-Edward E. Smissman Award of the American Chemical Society (2013), the Centenary Prize of the Royal Society of Chemistry (2013), and the Excellence in Medicinal Chemistry Prize of the Israel Chemical Society (2014). Professor Silverman has published over 320 research and review articles, holds 49 domestic and foreign patents, and has written four books (The Organic Chemistry of Drug Design and Drug Action is translated into German and Chinese). He is the inventor of LyricaTM, a drug marketed by Pfizer for epilepsy, neuropathic pain, fibromyalgia, and spinal cord injury pain; currently, he has another CNS drug in clinical trials.

Affiliations and Expertise

Northwestern University, Evanston, IL, USA

View additional works by Richard B. Silverman

Mark W. Holladay

Dr. Mark W. Holladay is Vice President of Drug Discovery and Medicinal Chemistry at Ambit Biosciences (San Diego, California) where he leads drug discovery programs in oncology and autoimmune diseases and has contributed to compounds in clinical development. He began his drug hunting career at Abbott Laboratories where he achieved the position of Volwiler Associate Research Fellow as a medicinal chemist and project leader in the Neurosciences Research Area. He also conducted collaborative drug discovery research as a member of contract research organizations including Biofocus and Discovery Partners International. He is a co-author on over 70 peer-reviewed research articles, reviews, or chapters and is named as an inventor on over 40 patents and patent applications. Dr. Holladay earned his undergraduate degree from Vanderbilt University, his Ph.D. at Northwestern University under the direction of Professor Richard B. Silverman, and conducted postdoctoral studies with Professor Daniel H. Rich at the University of Wisconsin-Madison.

Affiliations and Expertise

Ambit Biosciences, San Diego, CA, USA

The Organic Chemistry of Drug Design and Drug Action, 3rd Edition

1. Introduction
1.1. Overview
1.2. Drugs Discovered without Rational Design
     1.2.1. Medicinal Chemistry Folklore
     1.2.2. Discovery of Penicillins
     1.2.3. Discovery of Librium
     1.2.4. Discovery of Drugs through Metabolism Studies
     1.2.5. Discovery of Drugs through Clinical Observations
1.3. Overview of Modern Rational Drug Design
     1.3.1. Overview of Drug Targets
     1.3.2. Identification and Validation of Targets for Drug Discovery
     1.3.3. Alternatives to Target-Based Drug Discovery
     1.3.4. Lead Discovery
     1.3.5. Lead Modification (Lead Optimization)
 Absorption, Distribution, Metabolism, and Excretion (ADME)
 Intellectual Property Position
     1.3.6. Drug Development
 Preclinical Development
 Clinical Development (Human Clinical Trials)
 Regulatory Approval to Market the Drug
1.4. Epilogue
1.5. General References
1.6. Problems
2. Lead Discovery and Lead Modification
2.1. Lead Discovery
     2.1.1. General Considerations
     2.1.2. Sources of Lead Compounds
 Endogenous Ligands
 Other Known Ligands
 Screening of Compounds
      Sources of Compounds for Screening
           Natural Products
           Medicinal Chemistry Collections and Other "Handcrafted" Compounds
           High-Throughput Organic Synthesis
                Solid-Phase Library Synthesis
                Solution-Phase Library Synthesis
                Evolution of HTOS
      Drug-Like, Lead-Like, and Other Desirable Properties of Compounds for Screening
      Random Screening
      Targeted (or Focused) Screening, Virtual Screening, and Computational Methods in Lead Discovery
           Virtual Screening Database
           Virtual Screening Hypothesis
      Hit-To-Lead Process
      Fragment-based Lead Discovery
2.2. Lead Modification
     2.2.1. Identification of the Active Part: The Pharmacophore
     2.2.2. Functional Group Modification
     2.2.3. Structure-Activity Relationships
     2.2.4. Structure Modifications to Increase Potency, Therapeutic Index, and ADME Properties
 Chain Branching
 Conformational Constraints and Ring-Chain Transformations
     2.2.5. Structure Modifications to Increase Oral Bioavailability and Membrane Permeability
 Electronic Effects: The Hammett Equation
 Lipophilicity Effects
      Importance of Lipophilicity
      Measurement of Lipophilicities
      Computer Automation of log P Determination
      Membrane Lipophilicity
 Balancing Potency of Ionizable Compounds with Lipophilicity and Oral Bioavailability
 Properties that Influence Ability to Cross the Blood-Brain Barrier
 Correlation of Lipophilicity with Promiscuity and Toxicity
     2.2.6. Computational Methods in Lead Modification
 Quantitative Structure-Activity Relationships (QSARs)
      Historical Overview. Steric Effects: The Taft Equation and Other Equations
      Methods Used to Correlate Physicochemical Parameters with Biological Activity
           Hansch Analysis: A Linear Multiple Regression Analysis
           Manual Stepwise Methods: Topliss Operational Schemes and Others
           Batch Selection Methods: Batchwise Topliss Operational Scheme, Cluster Analysis, and Others
           Free and Wilson or de Novo Method
           Computational Methods for ADME Descriptors
 Scaffold Hopping
 Molecular Graphics-Based Lead Modification
     2.2.7. Epilogue
2.3. General References
2.4. Problems
3. Receptors
3.1. Introduction
3.2. Drug-Receptor Interactions
     3.2.1. General Considerations
     3.2.2. Important Interactions (Forces) Involved in the Drug-Receptor Complex
 Covalent Bonds
 Ionic (or Electrostatic) Interactions
 Ion-Dipole and Dipole-Dipole Interactions
 Hydrogen Bonds
 Charge-Transfer Complexes
 Hydrophobic Interactions
 Cation-p Interaction
 Halogen Bonding
 van der Waals or London Dispersion Forces
     3.2.3. Determination of Drug-Receptor Interactions
     3.2.4. Theories for Drug-Receptor Interactions
 Occupancy Theory
 Rate Theory
 Induced-Fit Theory
 Macromolecular Perturbation Theory
 Activation-Aggregation Theory
 The Two-State (Multistate) Model of Receptor Activation
     3.2.5. Topographical and Stereochemical Considerations
 Spatial Arrangement of Atoms
 Drug and Receptor Chirality
 Conformational Isomers
 Ring Topology
     3.2.6. Case History of the Pharmacodynamically Driven Design of a Receptor Antagonist: Cimetidine
     3.2.7. Case History of the Pharmacokinetically Driven Design of Suvorexant
3.3. General References
3.4. Problems
4. Enzymes
4.1. Enzymes as Catalysts
     4.1.1. What are Enzymes?
     4.1.2. How do Enzymes Work?
 Specificity of Enzyme-Catalyzed Reactions
      Binding Specificity
      Reaction Specificity
 Rate Acceleration
4.2. Mechanisms of Enzyme Catalysis
     4.2.1. Approximation
     4.2.2. Covalent Catalysis
     4.2.3. General Acid-Base Catalysis
     4.2.4. Electrostatic Catalysis
     4.2.5. Desolvation
     4.2.6. Strain or Distortion
     4.2.7. Example of the Mechanisms of Enzyme Catalysis
4.3. Coenzyme Catalysis
     4.3.1. Pyridoxal 5'-Phosphate
 Aminotransferases (Formerly Transaminases)
 PLP-Dependent ß-Elimination
     4.3.2. Tetrahydrofolate and Pyridine Nucleotides
     4.3.3. Flavin
 Two-Electron (Carbanion) Mechanism
 Carbanion Followed by Two One-Electron Transfers
 One-Electron Mechanism
 Hydride Mechanism
     4.3.4. Heme
     4.3.5. Adenosine Triphosphate and Coenzyme A
4.4. Enzyme Catalysis in Drug Discovery
     4.4.1. Enzymatic Synthesis of Chiral Drug Intermediates
     4.4.2. Enzyme Therapy
4.5. General References
4.6. Problems
5. Enzyme Inhibition and Inactivation
5.1. Why Inhibit an Enzyme?
5.2. Reversible Enzyme Inhibitors
     5.2.1. Mechanism of Reversible Inhibition
     5.2.2. Selected Examples of Competitive Reversible Inhibitor Drugs
 Simple Competitive Inhibition
      Epidermal Growth Factor Receptor Tyrosine Kinase as a Target for Cancer
      Discovery and Optimization of EGFR Inhibitors
 Stabilization of an Inactive Conformation: Imatinib, an Antileukemia Drug
      The Target: Bcr-Abl, a Constitutively Active Kinase
      Lead Discovery and Modification
      Binding Mode of Imatinib to Abl Kinase
      Inhibition of Other Kinases by Imatinib
 Alternative Substrate Inhibition: Sulfonamide Antibacterial Agents (Sulfa Drugs)
      Lead Discovery
      Lead Modification
      Mechanism of Action
     5.2.3. Transition State Analogs and Multisubstrate Analogs
 Theoretical Basis
 Transition State Analogs
      Forodesine and DADMe-ImmH
      Multisubstrate Analogs
     5.2.4. Slow, T ight-Binding Inhibitors
 Theoretical Basis
 Captopril, Enalapril, Lisinopril, and Other Antihypertensive Drugs
      Humoral Mechanism for Hypertension
      Lead Discovery
      Lead Modification and Mechanism of Action
      Dual-Acting Drugs: Dual-Acting Enzyme Inhibitors
 Lovastatin (Mevinolin) and Simvastatin, Antihypercholesterolemic Drugs
      Cholesterol and Its Effects
      Lead Discovery
      Mechanism of Action
      Lead Modification
 Saxagliptin, a Dipeptidyl Peptidase-4 Inhibitor and Antidiabetes Drug
     5.2.5. Case History of Rational Drug Design of an Enzyme Inhibitor: Ritonavir
 Lead Discovery
 Lead Modification
5.3. Irreversible Enzyme Inhibitors
     5.3.1. Potential of Irreversible Inhibition
     5.3.2. Affinity Labeling Agents
 Mechanism of Action
 Selected Affinity Labeling Agents
      Penicillins and Cephalosporins/Cephamycins
     5.3.3. Mechanism-Based Enzyme Inactivators
 Theoretical Aspects
 Potential Advantages in Drug Design Relative to Affinity Labeling Agents
 Selected Examples of Mechanism-Based Enzyme Inactivators
      Vigabatrin, an Anticonvulsant Drug
      Eflornithine, an Antiprotozoal Drug and Beyond
      Tranylcypromine, an Antidepressant Drug
      Selegiline (l-Deprenyl) and Rasagiline: Antiparkinsonian Drugs
      5-Fluoro-2'-deoxyuridylate, Floxuridine, and 5-Fluorouracil: Antitumor Drugs
5.4. General References
5.5. Problems
6. DNA-Interactive Agents
6.1. Introduction
     6.1.1. Basis for DNA-Interactive Drugs
     6.1.2. Toxicity of DNA-Interactive Drugs
     6.1.3. Combination Chemotherapy
     6.1.4. Drug Interactions
     6.1.5. Drug Resistance
6.2. DNA Structure and Properties
     6.2.1. Basis for the Structure of DNA
     6.2.2. Base Tautomerization
     6.2.3. DNA Shapes
     6.2.4. DNA Conformations
6.3. Classes of Drugs that Interact with DNA
     6.3.1. Reversible DNA Binders
 External Electrostatic Binding
 Groove Binding
 Intercalation and Topoisomerase-Induced DNA Damage
      Amsacrine, an Acridine Analog
      Dactinomycin, the Parent Actinomycin Analog
      Doxorubicin (Adriamycin) and Daunorubicin (Daunomycin), Anthracycline Antitumor Antibiotics
      Bis-intercalating Agents
     6.3.2. DNA Alkylators
 Nitrogen Mustards
      Lead Discovery
      Chemistry of Alkylating Agents
      Lead Modification
      (+)-CC-1065 and Duocarmycins
      Metabolically Activated Alkylating Agents
           Triazene Antitumor Drugs
           Mitomycin C
     6.3.3. DNA Strand Breakers
 Anthracycline Antitumor Antibiotics
 Enediyne Antitumor Antibiotics
      Esperamicins and Calicheamicins
      Dynemicin A
      Neocarzinostatin (Zinostatin)
 Sequence Specificity for DNA-Strand Scission
6.4. General References
6.5. Problems
7. Drug Resistance and Drug Synergism
7.1. Drug Resistance
     7.1.1. What is Drug Resistance?
     7.1.2. Mechanisms of Drug Resistance
 Altered Target Enzyme or Receptor
 Overproduction of the Target Enzyme or Receptor
 Overproduction of the Substrate or Ligand for the Target Protein
 Increased Drug-Destroying Mechanisms
 Decreased Prodrug-Activating Mechanism
 Activation of New Pathways Circumventing the Drug Effect
 Reversal of Drug Action
 Altered Drug Distribution to the Site of Action
7.2. Drug Synergism (Drug Combination)
     7.2.1. What is Drug Synergism?
     7.2.2. Mechanisms of Drug Synergism
 Inhibition of a Drug-Destroying Enzyme
 Sequential Blocking
 Inhibition of Targets in Different Pathways
 Efflux Pump Inhibitors
 Use of Multiple Drugs for the Same Target
7.3. General References
7.4. Problems
8. Drug Metabolism
8.1. Introduction
8.2. Synthesis of Radioactive Compounds
8.3. Analytical Methods in Drug Metabolism
     8.3.1. Sample Preparation
     8.3.2. Separation
     8.3.3. Identification
     8.3.4. Quantification
8.4. Pathways for Drug Deactivation and Elimination
     8.4.1. Introduction
     8.4.2. Phase I Transformations
 Oxidative Reactions
      Aromatic Hydroxylation
      Alkene Epoxidation
      Oxidations of Carbons Adjacent to sp2 Centers
      Oxidation at Aliphatic and Alicyclic Carbon Atoms
      Oxidations of Carbon-Nitrogen Systems
      Oxidations of Carbon-Oxygen Systems
      Oxidations of Carbon-Sulfur Systems
      Other Oxidative Reactions
      Alcohol and Aldehyde Oxidations
 Reductive Reactions
      Carbonyl Reduction
      Nitro Reduction
      Azo Reduction
      Azido Reduction
      Tertiary Amine Oxide Reduction
      Reductive Dehalogenation
 Carboxylation Reaction
 Hydrolytic Reactions
     8.4.3. Phase II Transformations: Conjugation Reaction
 Glucuronic Acid Conjugation
 Sulfate Conjugation
 Amino Acid Conjugation
 Glutathione Conjugation
 Water Conjugation
 Acetyl Conjugation
 Fatty Acid and Cholesterol Conjugation
 Methyl Conjugation
     8.4.4. Toxicophores and Reactive Metabolites (RMs)
     8.4.5. Hard and Soft (Antedrugs) Drugs
8.5. General References
8.6. Problems
9. Prodrugs and Drug Delivery Systems
9.1. Enzyme Activation of Drugs
     9.1.1. Utility of Prodrugs
 Aqueous Solubility
 Absorption and Distribution
 Site Specificity
 Prolonged Release
 Poor Patient Acceptability
 Formulation Problems
     9.1.2. Types of Prodrugs
9.2. Mechanisms of Drug Inactivation
     9.2.1. Carrier-Linked Prodrugs
 Carrier Linkages for Various Functional Groups
      Alcohols, Carboxylic Acids, and Related
      Amines and Amidines
      Carbonyl Compounds
 Examples of Carrier-Linked Bipartite Prodrugs
      Prodrugs for Increased Water Solubility
      Prodrugs for Improved Absorption and Distribution
      Prodrugs for Site Specificity
      Prodrugs for Stability
      Prodrugs for Slow and Prolonged Release
      Prodrugs to Minimize Toxicity
      Prodrugs to Encourage Patient Acceptance
      Prodrugs to Eliminate Formulation Problems
 Macromolecular Drug Carrier Systems
      General Strategy
      Synthetic Polymers
      Poly(a-Amino Acids)
      Other Macromolecular Supports
 Tripartite Prodrugs
 Mutual Prodrugs (also called Codrugs)
     9.2.2. Bioprecursor Prodrugs
 Proton Activation: An Abbreviated Case History of the Discovery of Omeprazole
 Hydrolytic Activation
 Elimination Activation
 Oxidative Activation
      N- and O-Dealkylations
      Oxidative Deamination
      Aromatic Hydroxylation
      Other Oxidations
 Reductive Activation
      Nitro Reduction
 Nucleotide Activation
 Phosphorylation Activation
 Sulfation Activation
 Decarboxylation Activation
9.3. General References
9.4. Problems
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