Real World Drug Discovery
A Chemist's Guide to Biotech and Pharmaceutical ResearchBy
- Robert Rydzewski
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 Chemists 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.
Graduate students and others moving into medicinal chemistry/pharma research, current drug discovery researchers, academic collaborators, and contract researchers.
Hardbound, 512 Pages
Published: September 2008
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 chemists 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, UKJOURNAL OF MEDICINAL CHEMISTRY, Volume 53, number 4: As explained in his preface, the purposes of [the authors] 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
- 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 EconomicsProblems A. Cost of Drug Development B. The Productivity Gap C. Market Withdrawals D. Generic Competition IV. Current EconomicsSolutions 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 ComeI. IntroductionII. 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 MedicineV. Summary References Chapter 3 Industrial ConsiderationsI. 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 TeamI. IntroductionII. 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 ReferencesChapter 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 GenerationI. Introduction II. Definitions III. Groups Involved IV. High-Throughput Screening A. History B. Myths and Truths about HTSV. 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 PropertiesI. 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 BindingIV. 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 PropertiesI. 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 DiscoveryI. 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. HopeReferences