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Structure-Guided Drug Design: Rediscovering the Importance of Drug Structure for Drug Discovery
Drug and Market Development Publishing, Nov 2004, Pages: 500
Chapter 1: Executive Summary 1–1
Why Structure-Guided Drug Design? 1–1
Current Status of the Pharmaceutical Industry 1–1
Classical and New Drug Discovery Paradigms 1–2
Receptors are the Major Drug Targets 1–3
Industrial and Virtual Drug Discovery 1–4
Modern Structure-Guided Drug Design 1–5
Drug Discovery by Design 1–5
Chapter 2: Drug Discovery In Context 2–1
The Drug Discovery Pipeline 2–1
Pipeline or Bottomless Pit? 2–2
Hormones are Endogenous Drugs 2–4
Increasing Pipeline Throughput 2–5
In silico Transformation of the Pipeline 2–7
Multiplexing and Parallel Processing 2–7
A Century of Drug Designs 2–8
Chemotherapy and Disease 2–8
Injury and Advances in Surgery 2–10
Invasion and the Antibiotic Boom 2–11
Intrinsic Failure 2–12
Health Farm-acology 2–13
Replacement Therapy 2–13
Metabolic Disease Therapy 2–14
Cancer Therapy 2–17
Breast Cancer Therapy 2–18
Cause for Hope? 2–21
The Drug Design Cycle 2–24
Effect-oriented Drug Discovery 2–24
Target-oriented Drug Discovery 2–26
Lead Structure Search and Lead Optimization 2–27
What is a Drug? 2–28
Molecular Properties 2–30
Uptake and Distribution 2–31
Clearance and Degradation 2–33
Activity and Toxicity 2–37
Druggability 2–39
Health of Modern Pharma 2–39
Drug Discovery in Context 2–40
References 2–40
Chapter 3: Hormones And Receptors 3–1
Hormones and Receptors 3–1
Hormones are Drugs Devised and Designed by Nature 3–2
Hormone Classification 3–2
The Message in the Molecule 3–4
The Hormone Stimulus Pyramid 3–7
Property Jumping 3–9
A Hormone-receptor System 3–15
Cysteine, Tyrosine, and Charge 3–18
Hormone-receptor Analytical Techniques 3–20
Physiological Bioassays In Vivo 3–21
Ligand Response Bioassays In Vitro 3–23
Ligand-binding assays 3–24
Isoform Analysis 3–26
Direct Physical Analysis 3–28
Life History of an Assay 3–28
Types of Assay 3–31
Tractable and In Vogue Assays 3–33
Molarity Range 3–33
Physical and Physiological Contexts 3–34
Drug Screening↓Effect- or Target-oriented? 3–35
Assay Emphasis Structure or Function? 3–38
Life History of the Hormone 3–38
Intracellular and Extracellular Trafficking 3–41
Assay Emphasis Minutes or Months? 3–42
Hormone Synthesis and Production 3–42
Target Tissue Responsivity 3–44
Reproductive Cyclicity 3–47
Life History of the Receptor 3–47
Receptors—Where Structure Meets Function 3–49
Ectopic Receptors and Vascular Endothelium Transfer 3–50
Receptor Promiscuity and Redundancy 3–50
Human Life Histories 3–52
Ontogeny and Phylogeny 3–54
hCG in Pregnancy and Cancer 3–55
Battle of the Genomes 3–57
Genomic Imprinting 3–59
Fetal Programming 3–60
(Re)productive Pharmacology 3–62
The Allometry Paradox… 3–62
…and Our Evolutionary Past 3–64
Placental Speciation 3–67
Assays in Context 3–69
References 3–70
Chapter 4: The Combinatorial Explosion or
High-Throughput Everything 4–1
The Concepts of In Dustrio Drug Discovery 4–1
Combinatorial Chemistry 4–2
Technology-driven HTS 4–4
From Molecules to Cells to Organelles 4–10
Modern Technologies and Biological Systems 4–10
From Common Salt to the Ribosome within a Century 4–11
The Protein Universe 4–13
High-throughput (target) Structure Initiatives 4–17
The Druggable Genome 4–18
Structural Genomics 4–19
Protein Structure Initiative Mission Statement (NIGMS, NIH) 4–21
Organization 4–22
Benefits 4–22
Membrane Receptors 4–25
High-throughput Protein Preparation 4–27
Tuning of Expression 4–27
Chemical Modification 4–27
Purification and Concentration 4–28
Macromolecular Analyses 4–30
Molecular Microscopy 4–30
Light Scattering (SAXS and WAXS) 4–32
X-ray Crystallography 4–33
Crystals and the Phase Transition Problem 4–34
Diffraction and the Phase Interpretation Problem 4–36
Molecular Modeling and Refinement 4–40
Modern Twists—Cryocrystallography 4–42
High-throughput Crystallography (HTX) 4–44
Crystallization Robots 4–44
Microfluidic Crystallization Chips 4–46
Automatic Crystal Changers 4–47
Automated Crystallographic Data Analysis 4–48
Nuclear Magnetic Resonance (NMR) 4–49
One-dimensional NMR 4–50
Multi-dimensional NMR 4–51
Assignments and 3D Structure Determination 4–52
NMR of Macromolecules (and Membrane Proteins) 4–53
High-throughput NMR? 4–54
Structure-based Lead Discovery 4–54
SAR by HTX 4–56
SAR by NMR 4–60
The Reliability of Structural Determinations 4–61
Model Verification and Quality 4–61
Comparing NMR and X-ray Determinations 4–63
Intracellular Receptors—ERα 4–65
Extracellular Hormones—hCG 4–71
Transmembrane Proteins—Rhodopsin 4–73
Structure in Context 4–76
From Where to Where? 4–76
References 4–78
Chapter 5: Molecular Interactions and Virtual Drug Design 5–1
The Concepts of in silico Drug Design 5–1
Ligand-receptor Interactions 5–2
In silico Transformation of the Discovery Pipeline 5–3
In silico in Water? 5–3
Molecular Properties of Water 5–4
Molecular Properties in Water 5–6
Amino Acids are not Peptides are not Proteins 5–7
Simple, Flexible and Complex Transitions 5–11
What is Binding? 5–12
Binding Models and the Law of Mass Action 5–13
Ligand-receptor Interactions Using Antibodies 5–15
Binding Kinetics 5–19
Size and Multicomponent Complexing 5–21
Positive or Negative Cooperativity? 5–25
The Intersect Affinity Profile 5–27
The Tangent Affinity Profile 5–27
Consequences of Simple, Flexible and Complex Binding 5–31
In vitro Binding Assays 5–31
Maturation of the Immune Response 5–34
Antibody Neutralization 5–35
Bioactivity and Therapy Consequences 5–37
Molecular Allometry 5–39
Ligands are Small and Receptors are Big 5–39
Theoretical Binding Maximum 5–42
Going Beyond 5–45
In silico Drug Design—Ligand-based 5–47
Chemoinformatics and Chemical Sense 5–47
Chemical Space and Diversity 5–49
Validation Assessment 5–52
Molecular Descriptors for Fingerprinting 5–54
Compound Classification 5–55
Focused Libraries 5–56
Predictions from QSPR 5–57
In silico Transformation of the Drug Discovery Pipeline 5–59
QSAR and the “Similarity Paradox” 5–61
3D Pharmacophores and 3D QSAR 5–62
ADME-Tox 5–65
Size and Surface 5–72
In silico Drug Design—Target-oriented 5–74
A Virtual Screen Reference 5–75
Virtual Screening Preparations 5–77
De novo Design 5–80
Docking 5–81
Scoring 5–83
Post-analysis 5–86
Docking and Scoring Comparisons 5–88
Protein Flexibility 5–92
Enrichment 5–95
Life on the Edge 5–95
In silico in context 5–97
Bioinformatics with Biological Sense 5–99
References 5–101
Chapter 6: The Modern Synthesis: Bringing It All Together 6–1
In dustrio Drug Discovery and in silico Drug Design 6–1
Holistic Enhancement and Synergy Strengths 6–2
Case Histories of Structure-Guided Drug Design 6–2
Virus Attack—HIV and Herpes Virus 6–4
AIDS and HIV 6–4
Chemokines and HIV entry Inhibitors 6–5
HIV Reverse Transcriptase and Integrase Inhibitors 6–8
HIV Protease Inhibitors 6–9
Herpes Virus, Kaposi’s Sarcoma (and hCG?) 6–10
HIV Combination Therapy 6–12
Virus Attack—SARS 6–13
SARS and Corona Virus 6–13
ACE2 is a SARS Receptor 6–14
Steroid Hormone Receptors 6–16
Receptor Cysteines and Hormone Binding 6–17
Receptor Cysteines and Ligand Screening 6–19
Receptor Activation and Cancer 6–23
Membrane Steroid Receptors are 7TMRs 6–25
Tyrosine Kinases 6–27
The Human Kinome 6–28
Discovery of Gleevec (STI571, imatinib mesylate) 6–30
Hematopoiesis and Leukemia 6–31
Philadelphia Chromosome and Bcr-Abl 6–32
c-Abl Kinase 6–34
c-KIT and GIST 6–36
PDGF Receptor and HES 6–38
Hitting a Moving Target—Mutation Resistance 6–39
Is Gleevec Unique or Just the Beginning? 6–41
Cystine-Knot Growth Factors 6–42
Convergent Growth Factor Evolution 6–42
Diverging Beyond 7TMRs 6–44
Ligand Convergence with RTKs and Cytokine Receptors 6–46
Diverging to RTKs Responsible for Growth and Death? 6–49
Receptor Serine Kinase Promiscuity 6–51
Developmental Receptors as Targets? 6–56
7TMRs 6–58
The Essence of Agonism 6–59
Ranking of Amino Acid Side Chains 6–61
Simple, Flexible and Complex Ligands 6–62
Receptor Activation Mechanisms 6–64
The Cysteine Shuffle 6–67
Drug Mechanisms and Targets 6–69
Tyrosine and Cysteine Molecular Switches 6–69
Redox Sensing, Priming, and Control 6–73
Toward a Universal Screening Assay? 6–76
Non-”Drug-like” Blockbusters 6–78
What is Bioactivity? 6–79
Agonism and Antagonism 6–80
Biomolecular Space 6–82
References 6–83
Chapter 7: Future Prospects 7–1
Structure-Guided Drug Design 7–1
Recurrent Themes 7–2
Small is Beautiful 7–3
Outsourcing Drug Properties 7–7
Audacious Targets: Simple, Flexible and Complex 7–10
SIMPLE—Pulsed Lasers 7–11
FLEXIBLE—Membrane receptors 7–14
COMPLEX—Functional Genomics? 7–16
Thinking Beyond 7–21
Breaking Barriers and Persistent Contamination 7–22
Gender and Sex 7–27
Birth, Death and Guinea Pigs 7–31
Thinking Big 7–33
Causes, Curses, and Cures 7–34
Public-private Consortia 7–39
Targeted Synergy Therapy 7–40
Drug Discovery by Design 7–42
Life on the Edge 7–43
Sustainable Growth 7–43
New Paradigms 7–45
References 7–46
Chapter 8: Companies To Watch 8–1
7TM PHARMA 8–2
Abbott Bioresearch Center 8–4
Accelrys Inc 8–6
AnorMED Inc 8–9
Antigenics Inc 8–11
artus GmbH 8–13
Astex Technology Ltd 8–14
Aurigene Discovery Technologies Limited 8–16
Biofocus plc 8–17
Bio-Xtal 8–19
Cengent Therapeutics Inc 8–20
Chemical Computing Group 8–22
Daylight Chemical Information Systems Inc 8–24
Evotec OAI AG 8–26
Fluidigm Corporation 8–28
INDIVUMED Center for Cancer Research 8–31
LifeSpan BioSciences Inc 8–32
Migenix Inc (formerly Micrologix Biotech Inc) 8–34
Structural GenomiX Inc 8–36
Sunesis Pharmaceuticals Inc 8–38
Synergix Ltd 8–40
Syrrx Inc 8–42
Tripos Inc 8–44
TABLE OF EXHIBITS
Exhibit 1 1 Structure-guided drug design is the modern exploitation of technology-driven
drug discovery and computer-driven drug design 1–1
Exhibit 1 2 Drug Discovery with 7TMRs will benefit from the decoding of agonist activity
and knowledge of the receptor activation mechanism 1–3
Exhibit 2 1 The drug discovery pipeline 2–2
Exhibit 2 2 Productivity gap between R&D dollars and new molecular entities 2–4
Exhibit 2 3 Preempting the drug development pipeline 2–6
Exhibit 2 4 Top 20 drugs targeting 7TMRs in worldwide sales during 2000 2–15
Exhibit 2 5 Incidence of various forms of cancer predicted for 2002 in the USA 2–18
Exhibit 2 6 Major therapeutic molecular targets in breast cancer 2–19
Exhibit 2 7 The drug design cycle 2–24
Exhibit 2 8 What is a drug? 2–29
Exhibit 2 9 Structures of cytochrome P450s with and without a substrate 2–34
Exhibit 2 10 Structures of 12-helix plasma membrane transporters 2–36
Exhibit 2 11 Drugs withdrawn recently because of adverse toxicity 2–38
Exhibit 3 1 Representative Ligands of 7TMRs and Features of their Sequence 3–3
Exhibit 3 2 Major hormones of the female reproductive axis 3–6
Exhibit 3 3 Molecular depictions of the four major types of receptor 3–12
Exhibit 3 4 The three major families of 7-transmembrane receptors 3–13
Exhibit 3 5 Molecular depictions of hCG and its interaction with the LH receptor 3–16
Exhibit 3 6 The common link in binding and response assays is the receptor molecule 3–17
Exhibit 3 7 Glycan flexibility revealed by molecular dynamics 3–19
Exhibit 3 8 Assays and nnalyses of hCG: from molecules to man 3–21
Exhibit 3 9 Timeline 1 life history of an assay: from physiology to molecular structure 3–30
Exhibit 3 10 Timeline 2 life history of a hormone: from production to degradation 3–40
Exhibit 3 11 Localizing the intracellular site of steroidogenic inhibition 3–45
Exhibit 3 12 Timeline 3 life history of the receptor: where structure meets function 3–48
Exhibit 3 13 Timeline 4 Human life history: from ontogeny to phylogeny and back 3–53
Exhibit 3 14 The absolute scale of the problem 3–63
Exhibit 3 15 Mammalian r and K reproductive strategies 3–65
Exhibit 3 16 Heterochrony in mammalian reproduction and development 3–67
Exhibit 4 1 Fluorescence correlation pectroscopy 4–5
Exhibit 4 2 Effects of membrane perturbants on binding 4–6
Exhibit 4 3 A cell-based screen with positive and negative controls in one well 4–9
Exhibit 4 4 From common salt to the ribosome within a century 4–12
Exhibit 4 5 Table of useful structural biology web sites 4–14
Exhibit 4 6 PDBsum web shot of the PDB Entry 1l9h for bovine rhodopsin 4–15
Exhibit 4 7 Functional conservation among major clusters in the protein universe 4–17
Exhibit 4 8 Table of SGI centers and companies 4–18
Exhibit 4 9 A flow diagram of a structural genomics project 4–20
Exhibit 4 10 Web shots of the TIGR and S2F structural genomics initiatives 4–24
Exhibit 4 11 Known membrane protein structures 4–26
Exhibit 4 12 Ribosome cryo-EM and docking of ab initio and X-ray 3D structures 4–31
Exhibit 4 13 Crystals and the unit cell of D radiodurans 50S ribosome 4–35
Exhibit 4 14 Braggs’ Law and diffraction patterns of the 50S ribosome 4–36
Exhibit 4 15 Wolfram clusters as big “heavy atoms” bound to protein extensions 4–38
Exhibit 4 16 RNA and protein compositions of the ribosome 4–39
Exhibit 4 17 Ramachandran plot and secondary structure for 1l9h rhodopsin 4–41
Exhibit 4 18 Automated and robotic crystallography systems 4–45
Exhibit 4 19 The Topaz Crystallizer Chip from Fluidigm 4–47
Exhibit 4 20 Companies with major HTX and NMR platforms 4–55
Exhibit 4 21 Neopterin sites in the tetrameric ting of the DHNA octamer cylinder 4–59
Exhibit 4 22 Domains of ERα and the Crystal Structure of the DBD and LBD 4–66
Exhibit 4 23 Different crystal structures of the nuclear receptor ERα 4–68
Exhibit 4 24 Leaching of cysteine reactants from PDB files 4–69
Exhibit 4 25 Predicted molecular structure of glycosylated hCG 4–71
Exhibit 4 26 Metal Ion and detergent stabilization of rhodopsin 4–74
Exhibit 4 27 Comparison of the X-ray crystal and NMR structures of rhodopsin 4–75
Exhibit 5 1 Hydrophobicity is the driving force behind the globular nature of proteins 5–7
Exhibit 5 2 Amphipathic peptides are flexible and their folding is context-sensitive 5–8
Exhibit 5 3 Amphipathic peptides can be membrane-permeant, lytic, or ionophores 5–10
Exhibit 5 4 Simple, flexible, and complex transitions in size and kinetics 5–11
Exhibit 5 5 Biomolecular interactions between hormones and antibodies 5–16
Exhibit 5 6 Simple, flexible and complex binding assays 5–17
Exhibit 5 7 Delayed addition of radioligand increases affinity in flexible and
complex assays 5–18
Exhibit 5 8 Association and dissociation kinetics of simple, flexible, and complex
ligands with antibody 5–20
Exhibit 5 9 Multicomponent complexing is inversely proportional to
antigen concentration 5–22
Exhibit 5 10 Derivation and assumptions of Scatchard analysis 5–25
Exhibit 5 11 Scatchard plots of protein interactions with a McAb and a PcAs 5–26
Exhibit 5 12 Binding affinity constants from curvilinear Scatchard plots 5–28
Exhibit 5 13 Decreasing positive cooperativity or increasing negative cooperativity
in ligand-receptor systems 5–30
Exhibit 5 14 Properties of radioimmunoassays that conform to simple, flexible,
and complex systems 5–32
Exhibit 5 15 Relative affinity considerations that conform to simple, flexible,
and complex systems 5–33
Exhibit 5 16 Neutralization by binding globulins or provision of a reserve? 5–37
Exhibit 5 17 Assay sensitivity coincides with in vivo hormone concentrations 5–38
Exhibit 5 18 The binding mode with antibody varies with the size of antigen 5–40
Exhibit 5 19 The maximal affinity of ligands 5–43
Exhibit 5 20 Major chemical structure databases 5–48
Exhibit 5 21 Molecular descriptors and a chemical global positioning system 5–51
Exhibit 5 22 Web shot of the BioRad integrated QSPR software solutions 5–59
Exhibit 5 23 Different solutions for in silico transformation of drug discovery 5–60
Exhibit 5 24 A 3D QSAR cage and distance-dependent energy functions 5–63
Exhibit 5 25 Flow diagram of ADME-Tox processes 5–66
Exhibit 5 26 Flexibility is common to promiscuous ADME-Tox proteins 5–68
Exhibit 5 27 Comparison of the ERα and PXR ligand-binding domains 5–69
Exhibit 5 28 Examples of ADME-Tox software solutions 5–71
Exhibit 5 29 From structure-based drug design to virtual screening 5–75
Exhibit 5 30 Thymidine kinase and ERα binding pockets 5–76
Exhibit 5 31 Virtual screening preparations, programs, and workflow 5–78
Exhibit 5 32 Implementation of a binding site algorithm 5–80
Exhibit 5 33 Ligand docking to a binding site 5–82
Exhibit 5 34 Binding constants for an 800-set of protein-ligand complexes 5–85
Exhibit 5 35 Features of the thymidine kinase binding pocket (1kim) 5–89
Exhibit 5 36 Stereotypical examples of protein flexibility 5–94
Exhibit 5 37 17β-estradiol binding pocket pharmacophore 5–96
Exhibit 5 38 Integrating disciplines and expertise in drug discovery for
bioinformatics with biological sense 5–100
Exhibit 6 1 Interventionist therapies in the HIV-1 life cycle 6–5
Exhibit 6 2 Promiscuity and profligacy of chemokines and their receptors 6–7
Exhibit 6 3 HIV-1 protease (1hbv) complexed with SB203238 6–10
Exhibit 6 4 Crystal structure of the SARS receptor ACE2 6–15
Exhibit 6 5 Molecular depictions of the LBD and DBD of ERα 6–18
Exhibit 6 6 Ligand-induced labelling of receptor using Cys-screen 6–20
Exhibit 6 7 Estradiol induces differential labelling of receptor cysteines 6–21
Exhibit 6 8 Redox control of cysteines in transcription factors and receptors 6–24
Exhibit 6 9 Different ground-states for 7TMRs 6–27
Exhibit 6 10 Representatives of the main human kinome families 6–28
Exhibit 6 11 Mechanisms of kinase repression and activation 6–29
Exhibit 6 12 STI571 binds to the inactive Abl conformation 6–33
Exhibit 6 13 Domain arrangements of Abl family tyrosine kinases 6–34
Exhibit 6 14 Structure and catalytic control of c-Abl tyrosine kinase 6–35
Exhibit 6 15 Phenotypic expression of germinal mutations in c-kit system 6–37
Exhibit 6 16 Variety of STI571-resistant mutations from a genetic screen 6–40
Exhibit 6 17 Dimerization topologies of cystine-knot growth factors 6–43
Exhibit 6 18 Cystine-knot growth factors and cognate receptor specificities 6–44
Exhibit 6 19 Receptor specificities of helical bundle and cystine-knot cytokines 6–47
Exhibit 6 20 Crystal structure of NGF and TrkA 6–50
Exhibit 6 21 Topology of the 2:2 BMP2-ligand/BMP1a-receptor complex 6–52
Exhibit 6 22 Ligand-receptor-antagonist stoichiometries at the cell surface 6–55
Exhibit 6 23 Binding of simple, flexible and complex ligands to 7TMRs 6–59
Exhibit 6 24 Olfactory and most gustatory receptors are 7TMRs 6–60
Exhibit 6 25 Venn diagram of amino acid propensities and reactivities 6–62
Exhibit 6 26 The four classes of hormone and their 7TMR binding 6–63
Exhibit 6 27 Contrasting views of a 7TMR and accessory molecules 6–66
Exhibit 6 28 Models of RNAse-RNI and of hCG interacting with its receptor 6–69
Exhibit 6 29 Metallothionein: keeping zinc ready for use 6–72
Exhibit 6 30 Reciprocal redox control of transcription factors and their gene products 6–74
Exhibit 6 31 Cysteine tethers and mapping of a binding pocket 6–77
Exhibit 6 32 Extended networks of cation−π and sulphur interactions 6–81
Exhibit 7 1 Recurrent themes in structure-guided drug design 7–3
Exhibit 7 2 Properties of the four main classes of hormone 7–4
Exhibit 7 3 Chemical compass for navigating biomolecular space 7–5
Exhibit 7 4 Property jumping by endocrine molecules 7–8
Exhibit 7 5 Structural determination of a single molecule in femtoseconds 7–11
Exhibit 7 6 Oversimplified complexes of cystine-knot and TNFα ligands 7–13
Exhibit 7 7 Genomic euphoria metaphors 7–20
Exhibit 7 8 A matter of life and death: p53 and mitochondria at the crossroads 7–37
Exhibit 7 9 Venn diagram of targeted synergy therapy 7–41
Exhibit 7 10 New pharma: sustainable long-term growth through R&D investment 7–44
Exhibit 7 11 Drug Discovery by Design 7–45
Exhibit 4 27 Comparison of the X-ray crystal and NMR structures of rhodopsin 4–75
Exhibit 5 1 Hydrophobicity is the driving force behind the globular nature of proteins 5–7
Exhibit 5 2 Amphipathic peptides are flexible and their folding is context-sensitive 5–8
Exhibit 5 3 Amphipathic peptides can be membrane-permeant, lytic, or ionophores 5–10
Exhibit 5 4 Simple, flexible, and complex transitions in size and kinetics 5–11
Exhibit 5 5 Biomolecular interactions between hormones and antibodies 5–16
Exhibit 5 6 Simple, flexible and complex binding assays 5–17
Exhibit 5 7 Delayed addition of radioligand increases affinity in flexible and
complex assays 5–18
Exhibit 5 8 Association and dissociation kinetics of simple, flexible, and complex
ligands with antibody 5–20
Exhibit 5 9 Multicomponent complexing is inversely proportional to
antigen concentration 5–22
Exhibit 5 10 Derivation and assumptions of Scatchard analysis 5–25
Exhibit 5 11 Scatchard plots of protein interactions with a McAb and a PcAs 5–26
Exhibit 5 12 Binding affinity constants from curvilinear Scatchard plots 5–28
Exhibit 5 13 Decreasing positive cooperativity or increasing negative cooperativity
in ligand-receptor systems 5–30
Exhibit 5 14 Properties of radioimmunoassays that conform to simple, flexible,
and complex systems 5–32
Exhibit 5 15 Relative affinity considerations that conform to simple, flexible,
and complex systems 5–33
Exhibit 5 16 Neutralization by binding globulins or provision of a reserve? 5–37
Exhibit 5 17 Assay sensitivity coincides with in vivo hormone concentrations 5–38
Exhibit 5 18 The binding mode with antibody varies with the size of antigen 5–40
Exhibit 5 19 The maximal affinity of ligands 5–43
Exhibit 5 20 Major chemical structure databases 5–48
Exhibit 5 21 Molecular descriptors and a chemical global positioning system 5–51
Exhibit 5 22 Web shot of the BioRad integrated QSPR software solutions 5–59
Exhibit 5 23 Different solutions for in silico transformation of drug discovery 5–60
Exhibit 5 24 A 3D QSAR cage and distance-dependent energy functions 5–63
Exhibit 5 25 Flow diagram of ADME-Tox processes 5–66
Exhibit 5 26 Flexibility is common to promiscuous ADME-Tox proteins 5–68
Exhibit 5 27 Comparison of the ERα and PXR ligand-binding domains 5–69
Exhibit 5 28 Examples of ADME-Tox software solutions 5–71
Exhibit 5 29 From structure-based drug design to virtual screening 5–75
Exhibit 5 30 Thymidine kinase and ERα binding pockets 5–76
Exhibit 5 31 Virtual screening preparations, programs, and workflow 5–78
Exhibit 5 32 Implementation of a binding site algorithm 5–80
Exhibit 5 33 Ligand docking to a binding site 5–82
Exhibit 5 34 Binding constants for an 800-set of protein-ligand complexes 5–85
Exhibit 5 35 Features of the thymidine kinase binding pocket (1kim) 5–89
Exhibit 5 36 Stereotypical examples of protein flexibility 5–94
Exhibit 5 37 17β-estradiol binding pocket pharmacophore 5–96
Exhibit 5 38 Integrating disciplines and expertise in drug discovery for
bioinformatics with biological sense 5–100
Exhibit 6 1 Interventionist therapies in the HIV-1 life cycle 6–5
Exhibit 6 2 Promiscuity and profligacy of chemokines and their receptors 6–7
Exhibit 6 3 HIV-1 protease (1hbv) complexed with SB203238 6–10
Exhibit 6 4 Crystal structure of the SARS receptor ACE2 6–15
Exhibit 6 5 Molecular depictions of the LBD and DBD of ERα 6–18
Exhibit 6 6 Ligand-induced labelling of receptor using Cys-screen 6–20
Exhibit 6 7 Estradiol induces differential labelling of receptor cysteines 6–21
Exhibit 6 8 Redox control of cysteines in transcription factors and receptors 6–24
Exhibit 6 9 Different ground-states for 7TMRs 6–27
Exhibit 6 10 Representatives of the main human kinome families 6–28
Exhibit 6 11 Mechanisms of kinase repression and activation 6–29
Exhibit 6 12 STI571 binds to the inactive Abl conformation 6–33
Exhibit 6 13 Domain arrangements of Abl family tyrosine kinases 6–34
Exhibit 6 14 Structure and catalytic control of c-Abl tyrosine kinase 6–35
Exhibit 6 15 Phenotypic expression of germinal mutations in c-kit system 6–37
Exhibit 6 16 Variety of STI571-resistant mutations from a genetic screen 6–40
Exhibit 6 17 Dimerization topologies of cystine-knot growth factors 6–43
Exhibit 6 18 Cystine-knot growth factors and cognate receptor specificities 6–44
Exhibit 6 19 Receptor specificities of helical bundle and cystine-knot cytokines 6–47
Exhibit 6 20 Crystal structure of NGF and TrkA 6–50
Exhibit 6 21 Topology of the 2:2 BMP2-ligand/BMP1a-receptor complex 6–52
Exhibit 6 22 Ligand-receptor-antagonist stoichiometries at the cell surface 6–55
Exhibit 6 23 Binding of simple, flexible and complex ligands to 7TMRs 6–59
Exhibit 6 24 Olfactory and most gustatory receptors are 7TMRs 6–60
Exhibit 6 25 Venn diagram of amino acid propensities and reactivities 6–62
Exhibit 6 26 The four classes of hormone and their 7TMR binding 6–63
Exhibit 6 27 Contrasting views of a 7TMR and accessory molecules 6–66
Exhibit 6 28 Models of RNAse-RNI and of hCG interacting with its receptor 6–69
Exhibit 6 29 Metallothionein: keeping zinc ready for use 6–72
Exhibit 6 30 Reciprocal redox control of transcription factors and their gene products 6–74
Exhibit 6 31 Cysteine tethers and mapping of a binding pocket 6–77
Exhibit 6 32 Extended networks of cation−π and sulphur interactions 6–81
Exhibit 7 1 Recurrent themes in structure-guided drug design 7–3
Exhibit 7 2 Properties of the four main classes of hormone 7–4
Exhibit 7 3 Chemical compass for navigating biomolecular space 7–5
Exhibit 7 4 Property jumping by endocrine molecules 7–8
Exhibit 7 5 Structural determination of a single molecule in femtoseconds 7–11
Exhibit 7 6 Oversimplified complexes of cystine-knot and TNFα ligands 7–13
Exhibit 7 7 Genomic euphoria metaphors 7–20
Exhibit 7 8 A matter of life and death: p53 and mitochondria at the crossroads 7–37
Exhibit 7 9 Venn diagram of targeted synergy therapy 7–41
Exhibit 7 10 New pharma: sustainable long-term growth through R&D investment 7–44
Exhibit 7 11 Drug Discovery by Design 7–45
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