TABLE OF CONTENTS
Chapter 1: Executive Summary .
- Why Structure-Guided Drug Design?
- Current Status of the Pharmaceutical Industry
- Classical and New Drug Discovery Paradigms
- Receptors are the Major Drug Targets
- Industrial and Virtual Drug Discovery .
- Modern Structure-Guided Drug Design
- Drug Discovery by Design
Chapter 2: Drug Discovery In Context
- The Drug Discovery Pipeline
- Pipeline or Bottomless Pit?
- Hormones are Endogenous Drugs
- Increasing Pipeline Throughput
- In silico Transformation of the Pipeline
- Multiplexing and Parallel Processing
- A Century of Drug Designs
- Chemotherapy and Disease
- Injury and Advances in Surgery
- Invasion and the Antibiotic Boom
- Intrinsic Failure
- Health Farm-acology .
- Replacement Therapy
- Metabolic Disease Therapy
- Cancer Therapy
- Breast Cancer Therapy
- Cause for Hope?
- The Drug Design Cycle
- Effect-oriented Drug Discovery
- Target-oriented Drug Discovery
- Lead Structure Search and Lead Optimization
- What is a Drug?
- Molecular Properties
- Uptake and Distribution
- Clearance and Degradation
- Activity and Toxicity .
- Druggability
- Health of Modern Pharma
- Drug Discovery in Context
- References
Chapter 3: Hormones And Receptors
- Hormones and Receptors
- Hormones are Drugs Devised and Designed by Nature
- Hormone Classification
- The Message in the Molecule
- The Hormone Stimulus Pyramid
- Property Jumping
- A Hormone-receptor System
- Cysteine, Tyrosine, and Charge
- Hormone-receptor Analytical Techniques
- Physiological Bioassays In Vivo
- Ligand Response Bioassays In Vitro .
- Ligand-binding assays
- Isoform Analysis
- Direct Physical Analysis
- Life History of an Assay
- Types of Assay
- Tractable and In Vogue Assays
- Molarity Range
- Physical and Physiological Contexts
- Drug Screening«Effect- or Target-oriented?
- Assay Emphasis Structure or Function?
- Life History of the Hormone
- Intracellular and Extracellular Trafficking
- Assay Emphasis Minutes or Months?
- Hormone Synthesis and Production
- Target Tissue Responsivity
- Reproductive Cyclicity
- Life History of the Receptor
- Receptors—Where Structure Meets Function
- Ectopic Receptors and Vascular Endothelium Transfer
- Receptor Promiscuity and Redundancy
- Human Life Histories .
- Ontogeny and Phylogeny
- hCG in Pregnancy and Cancer
- Battle of the Genomes
- Genomic Imprinting.
- Fetal Programming .
- (Re)productive Pharmacology
- The Allometry Paradox...
- ...and Our Evolutionary Past
- Placental Speciation
- Assays in Context
- References
Chapter 4: The Combinatorial Explosion or
- High-Throughput Everything
- The Concepts of In Dustrio Drug Discovery
- Combinatorial Chemistry
- Technology-driven HTS
- From Molecules to Cells to Organelles .
- Modern Technologies and Biological Systems
- From Common Salt to the Ribosome within a Century
- The Protein Universe
- High-throughput (target) Structure Initiatives
- The Druggable Genome
- Structural Genomics .
- Protein Structure Initiative Mission Statement (NIGMS, NIH)
- Organization
- Benefits
- Membrane Receptors
- High-throughput Protein Preparation
- Tuning of Expression .
- Chemical Modification
- Purification and Concentration
- Macromolecular Analyses
- Molecular Microscopy
- Light Scattering (SAXS and WAXS)
- X-ray Crystallography
- Crystals and the Phase Transition Problem
- Diffraction and the Phase Interpretation Problem
- Molecular Modeling and Refinement .
- Modern Twists—Cryocrystallography.
- High-throughput Crystallography (HTX) .
- Crystallization Robots
- Microfluidic Crystallization Chips
- Automatic Crystal Changers
- Automated Crystallographic Data Analysis .
- Nuclear Magnetic Resonance (NMR)
- One-dimensional NMR
- Multi-dimensional NMR
- Assignments and 3D Structure Determination
- NMR of Macromolecules (and Membrane Proteins)
- High-throughput NMR?
- Structure-based Lead Discovery
- SAR by HTX
- SAR by NMR
- The Reliability of Structural Determinations
- Model Verification and Quality
- Comparing NMR and X-ray Determinations
- Intracellular Receptors—ERƒ¿
- Extracellular Hormones—hCG
- Transmembrane Proteins—Rhodopsin
- Structure in Context.
- From Where to Where?
- References
Chapter 5: Molecular Interactions and Virtual Drug Design
- The Concepts of in silico Drug Design
- Ligand-receptor Interactions
- In silico Transformation of the Discovery Pipeline
- In silico in Water?
- Molecular Properties of Water
- Molecular Properties in Water
- Amino Acids are not Peptides are not Proteins
- Simple, Flexible and Complex Transitions .
- What is Binding?
- Binding Models and the Law of Mass Action
- Ligand-receptor Interactions Using Antibodies
- Binding Kinetics
- Size and Multicomponent Complexing
- Positive or Negative Cooperativity?
- The Intersect Affinity Profile
- The Tangent Affinity Profile
- Consequences of Simple, Flexible and Complex Binding .
- In vitro Binding Assays
- Maturation of the Immune Response
- Antibody Neutralization
- Bioactivity and Therapy Consequences
- Molecular Allometry
- Ligands are Small and Receptors are Big .
- Theoretical Binding Maximum
- Going Beyond
- In silico Drug Design—Ligand-based.
- Chemoinformatics and Chemical Sense
- Chemical Space and Diversity
- Validation Assessment
- Molecular Descriptors for Fingerprinting .
- Compound Classification
- Focused Libraries
- Predictions from QSPR
- In silico Transformation of the Drug Discovery Pipeline
- QSAR and the "Similarity Paradox"
- 3D Pharmacophores and 3D QSAR .
- ADME-Tox
- Size and Surface
- In silico Drug Design—Target-oriented
- A Virtual Screen Reference
- Virtual Screening Preparations
- De novo Design
- Docking
- Scoring
- Post-analysis
- Docking and Scoring Comparisons
- Protein Flexibility
- Enrichment
- Life on the Edge
- In silico in context
- Bioinformatics with Biological Sense .
- References
Chapter 6: The Modern Synthesis: Bringing It All Together
- In dustrio Drug Discovery and in silico Drug Design
- Holistic Enhancement and Synergy Strengths
- Case Histories of Structure-Guided Drug Design
- Virus Attack-HIV and Herpes Virus
- AIDS and HIV
- Chemokines and HIV entry Inhibitors
- HIV Reverse Transcriptase and Integrase Inhibitors
- HIV Protease Inhibitors
- Herpes Virus, Kaposi s Sarcoma (and hCG?)
- HIV Combination Therapy
- Virus Attack-SARS
- SARS and Corona Virus
- ACE2 is a SARS Receptor
- Steroid Hormone Receptors
- Receptor Cysteines and Hormone Binding .
- Receptor Cysteines and Ligand Screening .
- Receptor Activation and Cancer
- Membrane Steroid Receptors are 7TMRs .
- Tyrosine Kinases
- The Human Kinome
- Discovery of Gleevec (STI571, imatinib mesylate)
- Hematopoiesis and Leukemia
- Philadelphia Chromosome and Bcr-Abl
- c-Abl Kinase
- c-KIT and GIST
- PDGF Receptor and HES
- Hitting a Moving Target—Mutation Resistance
- Is Gleevec Unique or Just the Beginning?
- Cystine-Knot Growth Factors
- Convergent Growth Factor Evolution .
- Diverging Beyond 7TMRs
- Ligand Convergence with RTKs and Cytokine Receptors
- Diverging to RTKs Responsible for Growth and Death?
- Receptor Serine Kinase Promiscuity .
- Developmental Receptors as Targets?
- 7TMRs
- The Essence of Agonism
- Ranking of Amino Acid Side Chains
- Simple, Flexible and Complex Ligands
- Receptor Activation Mechanisms
- The Cysteine Shuffle
- Drug Mechanisms and Targets
- Tyrosine and Cysteine Molecular Switches .
- Redox Sensing, Priming, and Control
- Toward a Universal Screening Assay?
- Non-"Drug-like" Blockbusters
- What is Bioactivity?
- Agonism and Antagonism
- Biomolecular Space
- References
Chapter 7: Future Prospects
- Structure-Guided Drug Design
- Recurrent Themes
- Small is Beautiful
- Outsourcing Drug Properties
- Audacious Targets: Simple, Flexible and Complex
- SIMPLE—Pulsed Lasers
- FLEXIBLE—Membrane receptors
- COMPLEX—Functional Genomics?
- Thinking Beyond
- Breaking Barriers and Persistent Contamination
- Gender and Sex
- Birth, Death and Guinea Pigs
- Thinking Big
- Causes, Curses, and Cures
- Public-private Consortia
- Targeted Synergy Therapy
- Drug Discovery by Design
- Life on the Edge
- Sustainable Growth.
- New Paradigms
- References
Chapter 8: Companies To Watch
- 7TM PHARMA
- Abbott Bioresearch Center
- Accelrys Inc
- AnorMED Inc
- Antigenics Inc
- artus GmbH
- Astex Technology Ltd
- Aurigene Discovery Technologies Limited
- Biofocus plc
- Bio-Xtal
- Cengent Therapeutics Inc
- Chemical Computing Group
- Daylight Chemical Information Systems Inc
- Evotec OAI AG
- Fluidigm Corporation .
- INDIVUMED Center for Cancer Research
- LifeSpan BioSciences Inc
- Migenix Inc (formerly Micrologix Biotech Inc)
- Structural GenomiX Inc
- Sunesis Pharmaceuticals Inc
- Synergix Ltd
- Syrrx Inc
- Tripos Inc .
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