SPI Infoamtion

Table of Contents

Executive Summary

Introduction
Identifying hits: library design, virtual screening and fragment based
drug discovery
Innovations in biological assay development
ADME and toxicology in lead generation
Lead generation strategies in the pharma industry
R&D models, innovation and future success of lead generation

Chapter 1 Introduction

The drug discovery process: defining lead generation

Hit finding and verification
Hit optimization
Lead optimization
Criteria for potential lead compounds

Chemistry
Pharmacology
Absorption, Metabolism, Excretion, Distribution (ADME) and Toxicity

Chapter 2 Identifying hits: library design,virtual screening and fragment based drug discovery

Summary
Introduction
Hit to lead - identifying possible structures

Compound selection
Physiochemical properties
Chemical optimization and modification of hits

Engineering novelty

Beyond HTS - alternative methods for identifying hits
Fragment-based drug discovery

Companies involved in FBDD

Case study: deCODE chemistry & biostructures Inc
Case study: Zenobia Therapeutics

Can FBDD generate successful new drugs?
Technology improvements driving FBDD

Improving x-ray crystallography
Improvements in NMR spectroscopy for FBDD
High concentration biological assays
Improving biophysical methods
Improving fragment library design
Chemistry-based methods

HTS vs FBDD

Virtual screening

Target based virtual screening

Case study: Epix Pharmaceuticals'

When to use virtual screening
Target based virtual screening: challenges
Ligand based screening
Commercial virtual screening platforms

Conclusions

Chapter 3 Innovations in biological ass development

Summary
Introduction
Improving high throughput screening

Identifying valid hits
A quantitative approach to primary screening

Compound management and quality assessment
Dispensing

Informatics and data analysis

Improving in vitro assays for HTS

Surface plasmon resonance
Isothermal titration calorimetry and nanocalorimetry

Back-Scattering Interferometry

Differential scanning fluorimetry
High throughput Mass Spectrometry
Bio-layer interferometry

Innovations in cell-based assay technology

Automated confocal microscopy methods
Flow cytometry
Laser scanning cytometry
Label-free cell-based screens

Photonic crystal biosensors
Dynamic mass redistribution
Impedance-based whole cell biosensors

Other cell-based assays

Reverse arrays
Enzyme Fragment Complementation

HCS and SAR
Novel cell types and cultures

In vivo methods in lead generation

Zebrafish

Whole animal imaging and microscopy
Conclusions

Chapter 4 ADME and toxicology in lead generation

Summary
Introduction
Assessing ADME characteristics

Oral absorption
P-Glycoprotein interactions
Plasma protein binding
Clearance
Metabolic stability
Selectivity and off-target effects
Solubility

Toxicology at the lead generation stage

In silico structure-toxicity relationships
Chemoinformatic methods
Toxicogenomics
High content screening
Zebrafish
Whole animal imaging
Determining mutagenic and clastogenic potential
Measuring HERG liability
Investigating CYP inhibition and induction

Conclusions

Chapter 5 Lead generation strategies in the pharma industry

Summary
Introduction
Lead generation teams
Case studies

Bayer
Boehringer Ingelheim
Millennium Pharmaceuticals (Takeda)

Conclusions

Chapter 6 R&D models, innovation & fut success of lead generation

Summary
Introduction
R&D models: influence on lead generation

R&D models
Outsourcing and offshoring
Dealing with academia
Pharma collaboration - 'Co-opetition'

Innovation and the future

Targets and HTS
Focus on RNA
Focus on lead optimization
Nanochemistry - returning chemistry to its central role in drug discovery

Lead generation now and in the future

Chapter 7 Appendix

Primary research methodology
Acknowledgments
Glossary
Index
Bibliography

List of Figures
Figure 1.1: Pharma industry productivity decline (1999-2008)
Figure 1.2: Patent losses occurring between 2008-2014
Figure 1.3: The drug discovery process
Figure 1.4: Example of a lead generation workflow
Figure 1.5: Technologies involved in lead generation
Figure 2.6: Use of structural information in structure-based drug design
Figure 2.7: Examples of the chemical structures of compounds discovered using FBDD
Figure 2.8: ZoBio's target immobilized NMR spectroscopy method for fragment-based drug discovery
Figure 3.9: Areas of innovation in high throughput screening
Figure 3.10: Acoustic droplet ejection
Figure 3.11: Attributes required of software for HTS data storage and analysis
Figure 3.12: Kinetic characterization of 5 lead series using SPR (Biacore)
Figure 3.13: Bio-Layer Interferometry from ForteBio
Figure 3.14: Advantages of cell-based screening in HTS
Figure 3.15: Principle of detection: cell based assays with the Epic system from Corning
Figure 3.16 Principle of the EFC assay for a biochemical target: HitHunter from DiscoveRx
Figure 4.17: ADME and toxicology data available in high throughput assays
Figure 4.18: The Safety Intelligence Program from BioWisdom
Figure 4.19: Examples of assertions in the Safety Intelligence Program from BioWisdom
Figure 4.20: A typical toxicogenomics workflow in the pharma industry
Figure 5.21: Key innovations in lead generation technologies
Figure 5.22: Key activities of medicinal chemists during lead generation
Figure 5.23: ADME-Tox traffic light criteria in use at Bayer
Figure 5.24: Discovery-Assays-By-Stage paradigm of Millennium Pharmaceuticals
Figure 6.25: The microreactor-based lead discovery system

List of Tables
Table 2.1: Fragment-based drug discovery: the pros and cons
Table 2.2 Techniques used to assess fragment binding for FBDD
Table 2.3: Examples of companies with product pipelines derived from FBDD
Table 2.4: Examples of compounds discovered using FBDD
Table 2.5: Rule of Three criteria for a fragment library
Table 2.6: Examples of companies offering fragment libraries and collections for FBDD
Table 2.7: Examples of companies offering software for virtual screening
Table 3.8: Examples of companies providing software for HTS information storage and analysis
Table 3.9: Emerging technologies for high throughput screening
Table 3.10: A comparison of free-solution, label-free molecular interaction techniques
Table 3.11: Examples of recent collaborations between stem cell companies and big pharma for the use of stem cells in drug discovery research
Table 3.12: Advantages and disadvantages of zebrafish for compound screening
Table 3.13: Companies offering zebrafish screening products and services
Table 3.14: Advantages of molecular imaging of whole animals for preclinical studies
Table 3.15: Half lives of important positron emitting isotopes
Table 4.16: Examples of contract laboratories offering HCA cytotoxicity screening
Table 4.17: Examples of higher throughput or miniaturized versions of the Ames test
Table 6.18: Recent examples of academic drug discovery funding by big pharma