Medicinal Chemistry for Drug Discovery: Significance of Recent Trends

Medicinal Chemistry for Drug Discovery: Significance of Recent Trends

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. 
 

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

Tables and Figures

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