Summary
Structure-based drug design is perhaps the most elegant approach for discovering compounds exhibiting high specificity and efficacy. In reality, drug targets are very complex and this approach has had only limited utility. However, a number of recent successful drugs have in part or in whole emerged from a structure-based research approach.
Scope
This Report describes the many advances including crystallography and informatics that are behind these successes. The Report also discusses the impact these advances in structure-based drug design are likely to have on the economics of drug discovery.
Key Reasons to Buy
- Get a first-hand account of successful approaches to structure-guided drug design and the integration of classical and modern pharmacology from several descriptive case studies.
- Look inside 20+ companies utilizing structure-guided drug design for drug discovery, including their product pipelines, financial standing, partnerships & alliances, and more.
- Discover the future possibilities of structure-guided drug design from an overview of technologies on the horizon and their projected market impact.
- Gain insight into the biological systems in which drugs maneuver via an examination of hormones and receptors and how they operate.
- Obtain a complete picture of the history of drug discovery through a review of the smaller life cycles of drug development and the various life histories of particular drugs - from lead structure to market launch, from ingestion to excretion, and as a life-time brand on the market.
Company Profiles
- 7TM PHARMA
- Abbott Bioresearch Center
- Accelrys
- AnorMED
- Antigenics
- artus
- Astex Technology
- Aurigene Discovery Technologies
- Biofocus
- Bio-Xtal
- Cengent Therapeutics
- Chemical Computing Group
- Daylight Chemical Information Systems
- Evotec OAI AG
- Fluidigm Corporation
- Indivumed Center for Cancer Research
- LifeSpan BioSciences
- Migenix
- Structural GenomiX
- Sunesis Pharmaceuticals
- Synergix
- Syrrx
- Tripos
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�亟ffect- 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𦂤here 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䊼ryocrystallography.
- 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㜬R��
- Extracellular Hormones𤪔CG
- Transmembrane Proteins妔hodopsin
- 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葲igand-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𦝁arget-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𦳀utation 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𢰦ulsed Lasers
- FLEXIBLE𦳀embrane receptors
- COMPLEX䭻unctional 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 .
