Medicinal Chemistry for Drug Discovery

Summary

A thorough analysis of recent trends in medicinal chemistry and evaluation of their significance for advancing productivity in drug discovery is presented. This report includes:

• A critical evaluation of chemical and computational technological modalities, their current and potential value, and their commercial manifestations.
• A consideration of market dynamics with an emphasis on outsourcing and user views on the implications of current practices in drug discovery organizations.
• Insights gleaned from an extensive literature review, discussions with industry experts, and an opinion survey of personnel active in medicinal chemistry for drug discovery.

Medicinal Chemistry for Drug Discovery: Significance of Recent Trends reviews the state of the art and aims to determine the significance of technology and market trends in medicinal chemistry for advancing productivity in drug discovery. Although the fundamental task of medicinal chemists has not changed drastically over time, the chemical and computational tools and perspectives at their disposal have advanced significantly. One in particular, fragment-based drug design, stands out as promising major improvements in research productivity.

We examine medicinal chemistry-related approaches and methodologies that drug discovery organizations employ in an effort to increase productivity in early drug discovery and decrease attrition at later pipeline stages. Key topics considered include structure-based drug design, fragment-based drug design, natural products-based drug design, diversity-oriented synthesis, and chemogenomics. An overall assessment of the current and potential value of these approaches is presented. Various flavors of computer-aided drug design are also considered, as the complexity and limitations of drug discovery programs that are based on biochemical screens of large compound collections have been major factors in stimulating the growth of this modality.

Each of the aforementioned technological modalities is viewed in terms of practical examples and commercial activity. Outsourcing arises as a prominent theme in the applications realm, with special emphasis on companies with primary operations in countries with developing economies, notably China, India, and Russia. Among 32 companies considered, structure-based drug design is the most prevalent activity with most players emphasizing the fragment-based variation. Virtual screening is the second-most prevalent modality, whereas natural products, diversity-oriented synthesis, and chemogenomics appear in only a small minority of cases.

Outsourcing vendors are viewed according to participation in hit discovery, hit-to-lead synthesis, lead optimization, library synthesis, in-house drug discovery, and virtual drug design. More than one-third of the companies considered have operations primarily located in countries with emerging economies. A large majority of companies offer computer-based services, hit-to-lead, lead optimization, and library synthesis. Fewer engage in hit discovery, and a small minority do their own drug discovery.

Medicinal Chemistry for Drug Discovery: Significance of Recent Trends next examines deal activity and the influence of outsourcing on research productivity. Results from a survey of managers and researchers active in the field provide a multifaceted picture of practices and attitudes prevalent in drug discovery organizations today. Conclusions from the user survey highlight which modalities are viewed as having greater potential to make an impact on productivity. Finally, the complete transcripts of seven interviews with experts in the field are provided.

Contents

• Chapter 1
• Introduction
  • 1.1. Background
  • 1.2. Scope and Nature of The Report
• Chapter 2
• Evolution of Organic and Medicinal Chemistry in Pharma
  • 2.1. Pharmaceutical Trends over Time
  • 2.2. Combinatorial Chemistry
  • 2.3. Lipinski's Rule of Five
  • 2.4. Impact of Lipinski's Rule of Five
• Chapter 3
• Organic and Medicinal Chemistry Technologies for Drug Discovery
  • 3.1. Computer-Aided Drug Design
  • Virtual Screening
  • Target Structure-Based Design
  • Ligand Structure-Based Design
  • De Novo Compound Design
  • Qsar (Quantitative Structure-Activity Relationship)
  • Fragment-Based Drug Design
  • 3.2. Diversity-Oriented Synthesis in Drug Design
  • 3.3. Natural Products-Based Drug Design
  • 3.4. Chemogenomics and Drug Design
  • 3.5. Perspectives
• Chapter 4
• Applications of Organic and Medicinal Chemistry in Drug Discovery
  • 4.1. Overview of Technology Approaches of Outsourcing Vendors
  • 4.2. Overview of Service Offerings by Drug Discovery Outsourcing Vendors
  • 4.3. Structure-Based Drug Design
  • 4.4. Fragment-Based Drug Design
  • 4.5. Natural Products-Based Drug Discovery
  • 4.6. Diversity-Oriented Synthesis in Drug Discovery
  • 4.7. Virtual Screening
• Chapter 5
• Market Dynamics
  • 5.1. Outsourcing Dynamics
  • 5.2. Survey of Chemists and Managers Active in Medicinal Chemistry
  • Survey Conclusions
• Chapter 6
• Conclusions and Future Trends
  • 6.1. Optimizing The Interplay of Chemistry and Biology
  • 6.2. Effects of The Industrialization of Drug Discovery
• Chapter 7
• Expert Interviews
  • 7.1. Christopher Lipinski, Phd
  • Drug Discovery Consultant, Retired Senior Research Fellow, Pfizer
  • 7.2. Celerino Abad-Zapatero, Phd
  • Adjunct Professor, University of Illinois at Chicago, Center for Pharmaceutical Biotechnology
  • 7.3. Medicinal Chemistry Executive
  • Anonymous; Veteran from Big Pharma
  • 7.4. Gilbert Rishton, Phd
  • Founder and Director, Alzheimer's Institute, California State University Channel Islands
  • 7.5. Steven Muskal, Phd
  • Ceo, Eidogen-Sertanty
  • 7.6. Informatics Chemist
  • Anonymous; Big Pharma
  • 7.7. Sidney Topiol, Phd
  • Associate Director, Computational Chemistry, Lundbeck Research
• References
  • Company Index with Web Addresses
• Figures
  • Figure 3.1. The Molecular Diversity Spectrum
  • Figure 7.1. Pxr - Promiscuous Ligand-Binding Site
• Tables
  • Table 3.1. Examples of Drug Targets for Which High-Resolution X-Ray Structures Are Available
  • Table 4.1. Technological Approaches of Selected Drug Discovery Outsourcing Vendors
  • Table 4.2. Product/Service Offerings of Selected Drug Discovery Outsourcing Vendors
  • Table 4.3. Compounds Derived from Fragment-Based Drug Design Currently in Clinical Trials
  • Table 5.1. Selected Outsourcing Deals
  • Table 5.2. Survey Respondents by Job Position
  • Table 5.3. Survey Respondents by Job Function
  • Table 5.4. Involvement in Drug Discovery Chemistry
  • Table 5.5. Stages of Chemistry Involved in
  • Table 5.6. Current and Projected Involvement in Structure-Based Drug Design
  • Table 5.7. Current and Projected Involvement in Ligand-Based Drug Design
  • Table 5.8. Current and Projected Involvement in Quantitative Structure-Activity Relationship (Qsar)
  • Table 5.9. Current and Projected Involvement in Fragment-Based Drug Design
  • Table 5.10. Current and Projected Involvement in Natural Products-Based Drug Design
  • Table 5.11. Current and Projected Involvement in Diversity-Oriented Synthesis for Drug Design
  • Table 5.12. Current and Projected Involvement in Chemogenomics
  • Table 5.13. Significance of Approaches for Advancing Productivity
  • Table 5.14. Use of Virtual Screening in Selection of Screening Libraries
  • Table 5.15. Effect of Structure/Fragment-Based Design on Preclinical Success
  • Table 5.16. Effect of Structure/Fragment-Based Design on Phase Ii Success
  • Table 5.17. Extent of Natural Products Inclusion
  • Table 5.18. Influence of Natural Product Structures on Library Design
  • Table 5.19. Makeup of Libraries Selected for Primary Screens
  • Table 5.20. Contribution of Computer-Aided Drug Design
  • Table 5.21. Outsourcing Synthesis for Primary Screening Libraries
  • Table 5.22. Outsourcing Synthesis of Hit-to-Lead Libraries
  • Table 5.23. Outsourcing Synthesis for Lead Optimization
  • Table 5.24. Outsourcing Synthesis for Process Development
  • Table 5.25. Organic/Medicinal Chemistry Budget Expectations, 2009
  • Table 5.26. Organic/Medicinal Chemistry Budget Expectations, 3-Year Projection