Real World Drug Discovery

Description
This book provides a broad overview of the drug discovery process from the point of view of the research chemist. It explains many concepts involved in the science as well as the business of new medicines, defines essential terms, outlines important trends, and provides a macroscopic view of what really goes on in biotech and pharmaceutical research today. It fills a gap for many new researchers who need to quickly get up to speed on real world factors like project teams, intellectual property, consultants, etc., that were never presented to them in college, and will be useful to any scientist searching for timely insights into the fascinating world of drug discovery.

Table of Contents:

Chapter 1 – The Drug Discovery Business to Date
I. Introduction
II. The Past
A. Pharma Roots
B. Biotech is Born
C. The Genomics Revolution
III. Current Economics—Problems
A. Cost of Drug Development
B. The Productivity Gap
C. Market Withdrawals
D. Generic Competition
IV. Current Economics—Solutions
A. Pharma Profits and Market Expansion
B. Mergers and Acquisitions
C. Biotech Clinical Candidates to Pharma
D. Academic Contributions
E. Global Outsourcing
F. Blockbusters and Orphan Drugs
G. Repurposing
H. Chiral Switching
I. Combination Therapeutics
J. Reformulation
V. Summary
References

Chapter 2 – The Drug Discovery Business to Come
I. Introduction
II. New Models for Pharma
A. R&D Minus R
B. D Plus R
C. Smaller is Better
D. Specialty Drugs
E. Pricing Pressures and Price Controls
III. New Models for Academia and Biotech …
A. Translational Research
B. The Standard Biotech Model
C. “Is it a project or a company?”
D. Leaner, Meaner Startups
E. Biotech Alternatives
IV. New Technologies
A. S-Curves and Expectations
B. Genomics Redux
C. Personalized Medicine
D. Pharmacogenomics
E. Other “Omics”
F. The Adoption of Personalized Medicine
V. Summary
References

Chapter 3 – Industrial Considerations
I. Intellectual Property .. 1
A. The Value of New Ideas
1. Invention Disclosures
2. Notebooks and Data Recording
3. Avoiding Inappropriate Disclosure
B. Patents
1. Introduction and Definition
2. Patent Requirements
a. Novelty, Priority, and Prior Art
b. Unobviousness
c. Utility
3. Reading and Searching Patents
a. Some Preliminaries
b. Patent Anatomy
c. Locating Information in Patents
4. Inventorship
II. Outside Resources
A. Consultants
B. Academic or Government Research Agreements
C. Big Company-Small Company Collaborations
III. The New Drug R&D Process
A. Target Identification
B. Lead Identification
C. Lead Optimization
D. Preclinical
E. Stages in Clinical Development
F. What Are the Odds?
References

Chapter 4 – How Things Get Done: The Project Team
I. Introduction
II. The Project Team
A. The Project Goal
1. Compound Validation Goals
2. Target Validation Goals
B. Project Team Organization
1. The Matrix Management System
a. Day-to-Day Supervision
b. Target Compounds
c. Progress Reporting
d. Performance Evaluations
2. Project Team Roles
a. Project Team Leader
b. Project Team Member
c. Project Team Representative
d. Project Team Manager
C. Project Team Meetings
1. Meeting Scheduling
2. The Meeting Agenda
3. Meeting Notes
4. Action Items
5. Project Planning Tools
III. Conclusions
A. Summing Up
B. Is It Really Best?
C. The Benefits
References

Chapter 5 – Project Considerations
I. Introduction
II. Established Targets
III. Established “Tough Targets”
IV. Novel Targets
A. Identifying New Targets
B. Target Validation
1. Levels of Validation
2. Target Validation Tools
a. Knockouts and Knock-Ins
b. Antisense Oligonucleotides
c. RNAi
d. Antibodies
e. Aptamers
f. Small Molecules
C. Working on Novel Target-directed Projects
V. Targets Arising from Phenotype or High-Content Screening
A. Phenotype Screening Versus Target Screening
B. Elucidation of Phenotype Targets
VI. In Conclusion
References

Chapter 6 – Hit Generation
I. Introduction
II. Definitions
III. Groups Involved
IV. High-Throughput Screening
A. History
B. Myths and Truths about HTS
V. Approaches to Hit Generation
A. Random or Non-directed Methods
B. Screening of Synthetic Compound Collections
C. Screening of Combinatorial Diversity Libraries
D. Fragment Screening
1. Detecting Fragment Binding
2. Optimizing Fragment Hits
E. Screening of Natural Products and DOS Libraries
F. Directed or Knowledge-based Methods
1. Methods Based on Endogenous Ligands or Substrates
2. Methods Based on Other Leads
G. Computational Methods
References

Chapter 7 – Turning Hits into Drugs
I. What Now?
II. Biochemical Mechanisms in Hit Selection
A. Competition and Allostery
B. Irreversibility
C. Slow Off-rate Compounds
D. Why Mechanism Matters
III. Druglikeness
A. What Is It?
B. Predicting Drug-likeness
IV. Multidimensional Optimization
V. Lead Optimization Versus HTL
VI. Using Structure-Based Drug Design
A. Definition, History, and Goals
B. Potential Limitations
1. Conformational Flexibility
2. Other Limitations
C. Examples
1. HIV Protease Inhibitors
2. Other Examples
D. Working with Modelers
E. Conclusions
References

Chapter 8 – Initial Properties
I. Why Not All At Once?
II. Potency
A. What, Why, and How Much?
B. Species Specificity
III. Selectivity
A. Selectivity … Not!
B. Antitargets
IV. Structural Novelty
A. Bioisosteres, Group, and Atom Replacements
1. Definition and Utility
2. Examples
B. Scaffold Hopping, Morphing, and Grafting
C. Cyclization and Ring Opening
D. Other Methods
V. Solubility
A. Defining, Estimating, and Measuring Solubility
B. Problems Resulting from Poor Solubility
C. Improving Solubility
1. Molecular Modifications
2. Prodrugs
VI. Chemical and Plasma Stability
A. Definitions and Importance
B. Common Types of Instability
1. Oxidative Instability
2. Chiral Instability
3. Hydrolytic Instability
References

Chapter 9 – ADME and PK Properties
I. Cell Permeability and Absorption
A. Definitions
B. A Closer Look at Intestinal Absorption
C. Models of Cell Permeability and Absorption
1. Property-based Predictions
2. Immobilized Artificial Membranes
3. PAMPA
4. Caco-2 and Other Monolayer Assays
D. Improving Cell Permeability and Absorption
1. Molecular Modifications
2. Prodrugs
II. Metabolic Stability
A. Common Metabolic Transformation
1. Hydrolysis of Esters and Amides
2. Oxidations of Arenes, Alkenes, and Alkynes
3. Aliphatic Hydroxylation
4. Oxidations at or Adjacent to Heteroatoms
5. Glucuronidation
6. Overview
B. Assessing Metabolic Stability
1. Recombinant DMEs
2. Liver Microsomes
3. Liver Cytosol and S9
4. Hepatocytes
C. Improving Metabolic Stability
1. Metabolite Identification
2. Caveats
3. Structural Modifications
III. Plasma Protein Binding
A. Is It Important?
B. Measuring Plasma Protein Binding
C. Minimizing Plasma Protein Binding
IV. P-glycoprotein Interactions
A. Structure and Function
B. Types of P-gp Interactions
C. Measuring P-gp Interactions
D. Reducing P-gp Interactions

Chapter 10 – Toxicity-Related Properties
I. CYP Inhibition
A. Importance
B. Types of CYP Inhibition
C. CYP Inhibition Assays
D. Common Structural Features
E. Ways to Reduce CYP Inhibition
1. Reduce Lipophilicity
2. Remove or Replace Offending Features
3. Sterically Hinder Coordinating Nitrogens
4. Find a Way to “Insult” the CYP
II. CYP Induction
III. HERG Binding
A. Introduction
B. In Vitro Assays
C. Models of hERG Binding
D. Reducing hERG Interactions
IV. Mutagenicity
A. Background
B. Structural Aspects
References

Chapter 11 – A Career in Drug Discovery
I. Hiring: A Good Match
A. What Do Employers Want?
1. The Candidate Selection Process
a. The Resume
b. Recommendations
c. The Interview
2. Selection Criteria
B. What Should a Candidate Look For?
1. The Company
2. Compensation and Benefits
3. Some Questions To Ask
II. Assessing Performance
A. Evaluations
B. Promotions
III. The Long Haul: Perspectives
A. Job and Industry Evolution
B. The Evolution of a Research Career
C. Frustration
D. Hope
References