Real World Drug Discovery
A Chemist's Guide to Biotech and Pharmaceutical Research
- 1st Edition - July 7, 2010
- Latest edition
- Author: Robert M. Rydzewski
- Language: English
Drug discovery increasingly requires a common understanding by researchers of the many and diverse factors that go into the making of new medicines. The scientist entering the… Read more
Drug discovery increasingly requires a common understanding by researchers of the many and diverse factors that go into the making of new medicines. The scientist entering the field will immediately face important issues for which his education may not have prepared him: project teams, patent law, consultants, target product profiles, industry trends, Gantt charts, target validation, pharmacokinetics, proteomics, phenotype assays, biomarkers, and many other unfamiliar topics for which a basic understanding must somehow be obtained. Even the more experienced scientist can find it frustratingly difficult to get an overview of the many factors involved in modern drug discovery and often only after years of exploring does a whole and integrated picture emerge in the mind of the researcher.
Real World Drug Discovery: A Chemist’s Guide to Biotech and Pharmaceutical Research presents this kind of map of the landscape of drug discovery. In a single, readable volume it outlines processes and explains essential concepts and terms for the recent science graduate wondering what to expect in pharma or biotech, the medicinal chemist seeking a broader and more timely understanding of the industry, or the contractor or collaborator whose understanding of the commercial drug discovery process could increase the value of his contribution to it.
Real World Drug Discovery: A Chemist’s Guide to Biotech and Pharmaceutical Research presents this kind of map of the landscape of drug discovery. In a single, readable volume it outlines processes and explains essential concepts and terms for the recent science graduate wondering what to expect in pharma or biotech, the medicinal chemist seeking a broader and more timely understanding of the industry, or the contractor or collaborator whose understanding of the commercial drug discovery process could increase the value of his contribution to it.
- Interviews with well-known experts in many of the fields involved, giving insightful comments from authorities on many of the sub-disciplines important to cutting edge drug discovery.
- Helpful suggestions gleaned from years of experience in biotech and pharma, which represents a repository drug discovery "lore" not previously available in any book.
- "Periodic Table of Drugs" listing current top-selling drugs arranged by target and laid out so that structural similarities and differences are plain and clear.
- Extensive use of diagrams to illustrate concepts like biotech startup models, preteomic profiling for target identification, Gantt charts for project planning, etc.
Graduate students and others moving into medicinal chemistry/pharma research, current drug discovery researchers, academic collaborators, and contract researchers.
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
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
BRITISH TOXICOLOGY SOCIETY NEWSLETTER, Summer 2010 issue: "[I]lluminating and stimulating, as the author uses examples to demonstrate how the challenge of making new, profitable, drugs has changed in the last few years, as well as the shape of pharmaceutical companies themselves…. The relaxed writing-style of the author makes this book both very easy to read and enjoyable, while at the same time peppering the reader with new facts. Whereas the book is labeled as a chemist’s guide, I suspect that it would be of use to many people entering the drug discovery arena, be they chemists or not… Robert Rydzewski has succeeded in producing a text that will find its way onto the shelves of many early career-stage scientists, and I think they will be considerably improved by reading it."— Nick Plant, Centre for Toxicology, University of Surrey, UK
JOURNAL OF MEDICINAL CHEMISTRY, Volume 53, number 4: As explained in his preface, the purposes of [the author’s] treatise are to present new researchers "with a basic overview of how modern industrial drug discovery works", to introduce the relevant scientific disciplines, and "to provide some practical insights into common problems in drug discovery", and possible solutions. In my opinion, he has achieved these goals in an excellent manner. …This book is enthusiastically recommended to graduate faculty and students, to postdocs, recent graduates, young workers in the pharma industry, to anyone who would like a one-volume review of modern industrial drug discovery, and to the libraries that serve these groups. — Manfred E. Wolff, Intellepharm, Inc.
CHOICE, April 2009: "More than a primer, this book serves as an excellent introduction to research in industry in general and the pharmaceutical industry in particular, as well as a career resource ...Of particular interest to chemistry graduate students as well as research-orientated undergraduates and their mentors. Summing Up: Highly recommended."— R. E Buntrock, formerly, University of Maine
- Edition: 1
- Latest edition
- Published: July 7, 2010
- Language: English
RR
Robert M. Rydzewski
Over 24 years experience in industry including positions at: Celera Genomics, Gensia Pharmaceuticals, Syntex Corporation, Shell Development and G.D. Searle and Company.
Author of 21 papers, 12 patent applications and 2 book chapters.
Affiliations and expertise
Newark, CA, USARead Real World Drug Discovery on ScienceDirect