Management of Chemical and Biological Samples for Screening Applications E-Book
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- Herausgeber: Wiley-VCH
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Filling an obvious gap in the scientific literature, this practice-oriented reference is the first to tie together the working knowledge of large screening centers in the pharmaceutical and biotechnological field. It spans the entire fi eld of this emerging discipline, from compound acquisition to collection optimization for specific purposes, to technology and quality control. In so doing, it applies two decades of expertise gathered by several large pharmaceutical companies to current and future challenges in high-throughput screening. With its treatment of libraries of small molecules as well as biobanks containing biomolecules, microorganisms and tissue samples, this reference is universally applicable for any molecular scientist involved in a large screening program.
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Veröffentlichungsjahr: 2012
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Table of Contents
Related Titles
Title Page
Copyright
Dedication
Preface
List of Contributors
Chapter 1: Introduction to Sample Management
References
Chapter 2: Generating a High-Quality Compound Collection
2.1 Defining Current Screening Collections
2.2 Design Criteria for Enriching a Compound Collection with Drug-Like Compounds
2.3 Concluding Remarks
References
Chapter 3: Assessing Compound Quality
3.1 Introduction
3.2 Process Quality and Analytical Quality in Compound Management
3.3 Identity
3.4 Purity/Stability
3.5 Concentration/Solubility
3.6 Conclusions
Acknowledgments
References
Further Reading
Chapter 4: Delivering and Maintaining Quality within Compound Management
4.1 Introduction
4.2 What is Quality from a Compound Management Perspective?
4.3 Storage and Delivery of Samples in Solution
4.4 Intercepting Low Purity
4.5 Storage and Delivery of Solids
4.6 Automation Quality Control and Reliability
4.7 High-Quality Data Management
4.8 Conclusion
Acknowledgments
References
Chapter 5: Obtaining and Maintaining High-Quality Tissue Samples: Scientific and Technical Considerations to Promote Evidence-Based Biobanking Practice (EBBP)
5.1 Introduction
5.2 The Path toward Integration of Evidence-based Biobanking Practice
5.3 Integrating Evidence-based Biobanking Practice into Sample Protocols
5.4 Final Thoughts and Recommendations
References
Chapter 6: Thinking Lean in Compound Management Laboratories
6.1 The Emergence of ‘Lean Thinking’
6.2 The Application of ‘Lean Thinking’
6.3 Lean Thinking in Drug Discovery
6.4 A Lean Laboratory Toolbox
6.5 Streamlining Compound Processing – An Example
6.6 Summary
References
Chapter 7: Application of Supply Management Principles in Sample Management
7.1 Introduction
7.2 Common Pitfalls of Sample Management
7.3 Sample Management and Supply Chain Concepts
7.4 Implementing the Sample Management Strategy
7.5 Sample Management Organization
7.6 Sample Management Informatics
7.7 Avoid Monolithic Silos of Excellence
7.8 Position and Synchronize Inventory
7.9 Expand the Sample Management Boundary
7.10 Measuring and Assessing Effectiveness and Quality
7.11 Conclusions
References
Chapter 8: Solid Sample Weighing and Distribution
8.1 The Practicalities and Technology of Weighing Solid Compounds
8.2 Logistical Challenges of Transportation of Small Molecules
References
Chapter 9: Managing a Global Biological Resource of Cells and Cellular Derivatives
9.1 Introduction
9.2 Diversity of Collections
9.3 Sourcing and Acquisition
9.4 Authentication and Characterization
9.5 Cryopreservation, Storage, and Production
9.6 Data Management
9.7 Quality and Standards
9.8 Order Fulfillment and Distribution
9.9 Offsite Biorepository Management
9.10 Regulatory and Legal Compliance
9.11 Ownership and Intellectual Property Management
9.12 Collaborations
9.13 Conclusion
References
Chapter 10: Development of Automation in Sample Management
10.1 Introduction
10.2 Historical Background
10.3 Automation of Sample Management Today
10.4 System Building Blocks
10.5 Storage Systems
10.6 Liquid Handler
10.7 Accessories
10.8 Plate Handling, Integration
10.9 Case Study: Evolution of a Compound Management Group
10.10 Results
References
Chapter 11: Applications of Acoustic Technology
11.1 Introduction
11.2 Compound-Handling Challenges in Drug Discovery
11.3 Acoustic Drop Ejection – Performance, Quality Assurance, and Platform Validation
11.4 Acoustic-Assisted Compound Solubilization and Mixing
11.5 Acoustic Applications in Drug Discovery
11.6 Emerging Applications
References
Chapter 12: Enhancing Biorepository Sample Integrity with Automated Storage and Retrieval
12.1 The Emerging Growth of Biobanking
12.2 Automated Storage and Retrieval in a Biorepository
12.3 Configuration of an Automated Biorepository
12.4 Conclusions
References
Chapter 13: Information Technology Systems for Sample Management
13.1 Sample Registration
13.2 Intellectual Property and Laboratory Notebooks
13.3 Some Observations on Information Technology
13.4 Biological Data Management
Dedication and Acknowledgments
Chapter 14: Key Features of a Compound Management System
14.1 Why Do We Need Compound Management Information Technology Systems?
14.2 Compound Management Software
14.3 Benefits of Commercially Available Compound Management Systems
References
Chapter 15: What Does an HTS File of the Future Look Like?
15.1 Introduction
15.2 History of Compounds Collection for HTS
15.3 Impact of High-Throughput Chemistry on Corporate Files
15.4 Chemical Library Management
15.5 The Concept of Drug-Likeness and the Lipinski Rules
15.6 Quality versus Quantity
15.7 The Emergence of the Subsets: Fragment, G-Protein-Coupled Receptor (GPCR), Ion Channel, Kinase, Protein–Protein Interaction, Chemogenomics, Library Of Pharmacologically Active Compounds (LOPAC), Central Nervous System (CNS), and Diversity
15.8 Re-designing the Corporate File for the Future
15.9 Future Routes for Hit Identification
References
Chapter 16: New Enabling Technology
16.1 Introduction
16.2 A Drop-On-Demand Printer for Dry Powder Dispensing
16.3 Piezo Dispense Pens: Integrated Storage and Dispensing Devices and their Potential in Secondary Screening and Diagnostic Manufacturing
16.4 Future Directions in Acoustic Droplet Ejection Technology
16.5 Closing Remarks
References
Chapter 17: The Impact of Future Technologies within Biobanking
17.1 Introduction
17.2 The Role of Biobanks in Biomedical Research
17.3 The Increasing Complexity of Biobanking
17.4 Future Technologies and Biobanking: How Could New Technologies Affect the Daily Activities of Biobanks?
17.5 The Future of Biobanking Does Not Depend on Technological Developments Alone
17.6 Conclusions
Acknowledgments
References
Chapter 18: Outsourcing Sample Management
18.1 Outsourcing in the Pharmaceutical Industry
18.2 Outsourcing Biological Specimen Collections
18.3 Conclusions
Acknowledgments
References
Chapter 19: Sample Management Yesterday and Tomorrow
19.1 The Role of Sample Management
19.2 Automation of Compound Management
19.3 Compound Integrity
19.4 Reduction of Redundancy
19.5 The Future of Sample Management?
19.6 Concluding Remarks
References
Index
Related Titles
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2010
ISBN: 978-0-470-19115-6
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Identification and Optimization of Drug-like Molecules
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ISBN: 978-3-527-32331-9
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The Editors
Dr. Mark Wigglesworth
GlaxoSmithKline
Medicines Research Centre
Gunnels Wood Road
Stevenage
Hertfordshire
SG1 2NY
United Kingdom
Dr. Terry Wood
TP & AAW Consultancy
8, Arundel Road
Cliftonville
Kent, CT9 2AW
United Kingdom
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Dedication
We would first like to thank everyone that has contributed to this book and hope that it is a text which helps promote and project forward the science of Sample Management. We have both found our work within the pharmaceutical industry rewarding not least because it is an opportunity to make the medicines that help other people. To this end we pledge our editorial honoraria to Cancer Research UK, which is a beneficiary close to both our hearts. Finally we would like to dedicate this work to our families; we thank them for their patience and hope that we have made this world a better place for them.
The royalties from the sale of this book will be donated to Cancer Research UK.
Cancer Research UK is the world's leading cancer charity dedicated to saving lives through research. Our ground breaking work into the prevention, diagnosis and treatment of cancer has seen survival rates double in the last 40 years. But more than one in three of us will still get cancer at some point in our lives. Our research, entirely funded by the public, is critical to ensuring more people beat it.
The views and opinions within this book are those of the Authors, and are independent from the work of Cancer Research UK.
Preface
Within this book we present a modern, practice-orientated overview of concepts, technology, and strategies for the management of large entity collections, encompassing both chemical and biological samples. This book reports expert opinion in this area and documents the evolution, current best practice, and future goals of Sample Management in a form never previously achieved.
The field of Sample Management has evolved in the last 20 years from a necessary, if somewhat haphazard, occupation of a screening scientist into a highly controlled, scientific discipline, incorporating logistics and automation management. This evolved scientific discipline is a pivotal part of every pharmaceutical and biotechnological organization across the globe, yet holding these samples in huge warehouses has no intrinsic value in itself. The samples must be subjected to High-Throughput Screening, population-based clinical research, and/or many other techniques that form part of the drug discovery pipeline before that one single chemical structure is identified which will lead to a life-changing discovery (see Figure 1). These single samples, at the end of many years of research, are the ones of value, and nurturing them and ensuring that you are able to find them within your collection is the role of the Sample Manager.
Figure 1 A schematic showing Sample Management as a contributor to drug discovery: only when many elements work cohesively together can the value in what we do be realized.
This book will guide the reader through the complex paths of Sample Management, starting with a view of what it represents for both chemical and biological samples and the reasons why this discipline has had to be developed. We present views on sample quality and the importance of quality in both establishing collections and maintaining them once created. We present the rationale for the subdivision of collections for efficient screening, and provide an overview of automation, from large-scale storage devices through to bench-top liquid handling technology for compound dispense. We further examine the latest and most advanced technologies available and how these are being implemented within the industry. Rarely do organizations exist in isolation; hence we examine the logistics of sample storage and transportation, taking in the practical and legal elements. One of the biggest potential issues within Sample Management is the tracking of data and samples within an inventory, from sample receipt through dissolution, dispense, and utilization. An IT system that interacts with automation and tracks the movement of every sample is key to establishing reliable delivery of samples and data integrity. Hence, we present two chapters introducing bespoke database systems through to examples of the off-the-shelf systems that fulfill this need.
In order to survive in an increasingly complex business environment, many companies are turning to process efficiency techniques that were made popular by the automotive industry, such as LeanSigma. Sample Management has many similarities to a production activity, and hence we examine these new techniques and show how they can be applied to improve process efficiencies and deliver key insights. In a further drive for efficiency, the pharmaceutical industry has focused on reducing attrition. This in turn has focused on changing the chemical properties of small-molecule collections, leading to new thought on how collections should be generated.
For the management of biological samples, which present their own, unique set of issues, we examine the challenges of obtaining tissues of high and comparable quality, looking at automation currently in use in this field as well as examining the potential of future technologies to assist biobanking. Tissue biobanking as well as the management of biological materials in the form of cell lines used within biological assays is discussed. We finish with a projected view of Sample Management, where outsourcing opportunities have delivered benefits to both chemical and biological sample management organizations and how utilization of the skills within Sample Management facilitate operating large scale processes. We also offer opinion on what the Sample Management department of the future might look like and how alterations in the drug discovery process may affect the process of Sample Management.
Above all we hope that this book will be a useful tool for any Sample Management organization, large or small, and will challenge you to take a fresh look at your organization and what it is doing. Think not just about how you will fulfill the next request, but also how you, in your role as a Sample Manager, can continue to expedite the essential business of drug discovery in years to come.
United Kingdom, November 2011
Mark Wigglesworth, Terry Wood
List of Contributors
1
Introduction to Sample Management
William P. Janzen and Andy Zaayenga
At its simplest level sample management is just inventory – where can one find a given item and retrieve it? But in the context of modern discovery efforts, be they drug discovery, agricultural, protein therapeutic, biobanking, or the plethora of other disciplines that collect and manage samples, the problem is far more complex. Today, sample management may have to manage millions of samples in a library that spans several continents but will also have to contend with a worldwide customer base. To make the problem more difficult the content of the samples must also be managed, which may involve complex chemical structures and storage conditions that may vary from room temperature under inert atmosphere to storage in liquid nitrogen. At this level the storage of these samples must now involve complex informatics and automation systems. This volume will capture the best practices compiled from experts in the field of sample management and will hopefully serve as a guide to both novice sample managers who need to track a few thousand compounds in room-temperature vials to professionals in multinational organizations.
As long as there have been chemicals there has been a need for sample management. One could imagine that for a seventeenth century druggist this was simply an inventory of the herbal extracts and remedies he compounded into salves and potions and the location where they were stored. This could be done from memory in most cases and probably evolved to a written inventory when searching for needed components became too slow and cumbersome. Early sample management evolved in parallel with drug discovery. What we consider sample management today came into being as pharmaceutical companies began to amass chemical libraries and test these in disease-focused assays. As these companies synthesized compounds, they retained samples and began to amass collections of chemical compounds that numbered in the tens of thousands. At the same time, the testing of natural product extracts became common practice, significantly boosting the number of samples to be stored [1, 2]. As the number of samples exceeded 100 000 (at that time a seemingly immense number), automated systems were developed to store and catalog them. Initially, these were simple robotic units or adapted card file systems that would simply present entire drawers or boxes of samples to an operator. Chemical structures were often still paper copies and stored elsewhere, and the amount in the inventory was rarely accurate if tracked at all. Storage labware formats were standardized to accommodate the large volumes of samples moving through the system and to facilitate liquid handling and detection platform development [3]. Improvements in liquid handling and detection enabled increasingly higher labware densities, allowing tighter environmental control, and larger libraries.
Sample integrity became paramount with a focus on environmental conditions and consistent sample history both in the storage units and in the reformatting/analysis areas. Significant numbers of legacy compounds which had been subjected to variable temperatures, water, oxygen, and light were found to be compromised. Container seal adhesives and labware mold components could introduce interferents to the assay results. Compound managers realized that consistent sample quality was a key to valid scientific data. Programs were employed to provide cradle-to-grave care as well as purity monitoring to insure repeatable sample integrity.
With the advent of combinatorial chemistry, parallel synthesis made the creation of large compound sets numbering in the hundreds of thousands viable and raised the stakes for compound management. High-throughput screening (HTS) groups began requiring that compounds be presented in 96 well plates dissolved in Dimethyl sulfoxide (DMSO) and consumed these plates at an alarming rate. At about the same time, the electronic storage and representation of chemical structures became possible [4]. As the numbers of samples increased, chemists could no longer rely on visual inspection of structures, so tools were developed to analyze synthetic sets to determine their degree of similarity or difference [5]. Compound management groups, that had often become underfunded corporate backwaters, suddenly found themselves under the spotlight as the bottleneck in an exciting new process.
In answer to this challenge, funding was allocated to revamp chemical stores, and a plethora of bespoke systems of automation and data management appeared [1, 6–8]. The linkage between automated preparation systems and data systems was a slow process and the systems that were created varied widely in their architecture and success but shared a number of traits that embody today's samples management system:
Sample registration
Usage of enterprise-wide standardized labware
Positive sample tracking, usually using barcodes
Cradle-to-grave tracking of samples stored in both vials and plates
Sample security with user access tracking and control
Accurate quantity tracking of both mass and volume
Storage of compounds in DMSO solutions
Control of environmental conditions to minimize water uptake, oxygen and light degradation, and temperature fluctuation
High speed automated storage and retrieval
Reduced freeze/thaw cycles by efficient daughter plate production or by multiple aliquotting
Regular purity monitoring
Sample ordering systems
Automated cherry picking and plate preparation systems
Robust distribution methods and sample tracking outside of the storage system.
As HTS and ultra high throughput screening (uHTS) became ubiquitous tools in drug discovery, they also began to be used in other industries such as the discovery of agricultural agents (pesticides, animal health, etc.), catalysts, polymer discovery, fragrances, and flavorings. Similarly, the newly created science of sample management also found utility in many other areas. With the advent of the human genome project the need to store large numbers of biological samples became imperative [9]. Blood and tissue sample banks both for research and distribution grew to the point where they required similar techniques (Table 1.1). Today sample management is applied in industries as varied as hospital pharmacies, environmental repositories, and sperm banks. So let us now examine the techniques used in modern sample management.
Table 1.1 Comparison of compound management and biobanking.
Compound management
Biobanking
Compounds are precious but for the most part replaceable
Specimens irreplaceable
Freeze/thaw cycles kept low, target 6–10
Freeze/thaw cycles very low or none
Large legacy libraries to be automated, which were added to en masse through library purchase or acquisitions/mergers
Small collections, few legacy specimens to be automated, samples added incrementally
Unregulated environment, compliance requirements low
Regulated environment, compliance requirements high
Low probability of cross organization exchange
High probability of cross organization exchange
Historically large budgets for R&D, low examination of return on investment (ROI), long-term funding available
Costs and resources may be subsidized, budgets and ROI examined closely, long term financing to cover length of studies difficult
Quality of legacy samples questionable
Quality of legacy samples questionable
Inventory: Probably the most critical factor in sample management remains inventory. But this has expanded well beyond the simple ‘where is it’ definition. Today's sample manager is more concerned with curation of the samples in their charge. As is discussed in Chapters 2–4, this includes the integrity of the samples on receipt, during storage, and even after delivery to end customers. To accomplish this, samples must be subjected to analytical tests for quality control (QC). In many cases this information will be provided by the supplier of the material. When that supplier is an internal group or a trusted partner this may be deemed sufficient and accepted but in other cases the purity of the material will have to be verified. For small molecule samples the most common method applied is Liquid Chromatography/Mass Spectrometry (LC/MS) analysis [10, 11].
In biobanking, the focus is on maintaining quality from collection to analysis. Here the primary problem is that one cannot sample the specimen regularly due to degradation during the aliquoting process. Also, the specimen volume is likely to be very small and therefore prized. Establishing the purity on receipt is a critical first step but is rarely sufficient. The quality of the samples in storage must be verified over time and, in many cases, after dissolution. The latter remains a largely unsolved problem as of the time of this writing. Dissolving a compound introduces a host of QC problems, particularly when the samples are transferred to plates. While it is possible to test the concentration and purity of samples dissolved in DMSO, it is not practical to test hundreds of thousands of samples on a regular basis using these techniques. In addition, it is nearly impossible to test small-molecule chemical samples in the environment used for HTS. Representative sampling of libraries has shown that a relatively high proportion (>20%) of the compounds in a sample set will be insoluble after a simple water dilution [12]. On the other hand, empirical data shows that many of these compounds will show activity in certain buffer or cellular testing systems implying that they are soluble under alternative conditions. The solution that many laboratories have adopted is to test subsets of the library and to test compounds that are determined to be active and are requested for further follow up. This approach is discussed in more detail in Chapters 2 and 15.
To make the problem even more complex, the samples may be subjected to various storage conditions and may be shipped to alternative sample management sites or end customers. The number of times the sample has been frozen and thawed and the storage temperatures may affect the stability of the sample set. There is not a clear body of literature on sample stability in DMSO [13, 14] and conflicting anecdotal evidence making the choice of storage conditions for DMSO samples difficult. The unusual physical properties of DMSO also complicate this matter [15]; DMSO will readily absorb water and oxygen from the atmosphere, which radically changes its freezing point and may affect the stability of compounds. The range of approaches in this area is widely varied. Some groups have established maximum freeze/thaw ranges and employ single-use plates in their process to minimize atmospheric exposure, while others have embraced room temperature storage and accepted the inevitability of water uptake by adding 10–20% water to their DMSO prior to sample dissolution [16–18]. This broad range of approaches and the fact that all have produced lead compounds makes establishing a true best practice impossible.
Tracking the location and history of samples is neither simple nor taken for granted. The use of barcodes is ubiquitous in sample management today. Barcodes are, in essence, very simple; they are simply a way of recording a serial number and rapidly and accurately entering that into a computer system. Barcode-based inventory systems, on the other hand, can be quite complex [19, 20]. They require the assignment of a tracking ID to every sample and a complex data model to register every manipulation of a sample from weighing through solubilization and any transfer from container to container. This system must always have not only the current volume of every sample but the historical record of every transfer from the lot submitted to the disposal of the last plate.
Data systems supporting sample management are discussed in Chapters 13 and 14. In addition to inventory, they will usually incorporate some mechanism for managing requests for samples. Customer ordering systems should always appear simple to end customers but may have quite complex internal management structures for the sample management professional. This can include ‘pull’ systems, where customer ordering software allows users to request samples and specify form (i.e., solid or liquid and concentration) and even location on a plate. Other aspects of a system may employ ‘push’ systems that automatically assign work to be performed on samples. For example, chemical samples that are synthesized as part of a specific medicinal chemistry program will usually have a prescribed group of assays that need to be conducted on each compound. When a chemist submits compounds, he or she may associate the molecules with a given program, and the IT system will automatically create work orders that create plates, tubes, and/or vials that are routed to the laboratories performing these tests.
The final aspect of sample management is automation systems, found in Chapters 10 and 12. While the management of samples does not require automation, it is virtually impossible to support the management of a large library without some degree of automation. Automated systems can range from simple liquid handling units that perform vial-to-plate transfers and plate-to-plate replication to large fully integrated systems that can perform all the aspects of sample preparation from sample dissolution to final microplate preparation. It should be noted that the one aspect of sample management that has never been efficiently automated is the weighing of samples. While significant resources have been devoted to this problem, automated solutions have been stymied by the highly varied nature of the chemical samples themselves. These samples can range from very dry, free flowing powders (which are easy to dispense) to tars that must be scraped or transferred by dipping a spatula, or proteins that are extremely hygroscopic and form light flakes that blow away easily. As a result almost all laboratories still employ a manual weighing process that is highly integrated with a data system and sample tracking to ensure accuracy – this is another reason that QC is so important. As with many HTS applications, this aspect of sample management has largely been solved. The systems have evolved from gymnasium-sized units that could store 1 million samples and process 10 000–20 000 samples per day to small unit stores that can be connected to provide the same storage capacity in a standard laboratory. Similarly, the problem of low-temperature storage has largely been solved. Systems that operate at temperatures down to vapor phase liquid nitrogen storage are now available and are discussed in the biobanking sections of this volume. Modern sample management systems enable the automated storage of virtually any sample from small-molecule chemicals to cells and tissues.
So, in conclusion, the field of sample management has grown both in importance and sophistication. The importance of this activity cannot be underestimated. The cost to replace a corporate chemical collection can be conservatively estimated at $500 per sample. For a 1 million compound collection this might take four to five years and cost $500 000 000. Additionally, human and non-human biological specimens are irreplaceable. Even if a replacement specimen can be obtained, the biological state will have changed and the specimen will not be identical. When looked at in this light, it would be criminal to allow compounds or specimens to degrade or be lost.
References
1. Archer, J.R. (2004) History, evolution, and trends in compound management for high throughput screening. Assay Drug Dev. Technol., 2 (6), 675–681.
2. Janzen, W.P. and Popa-Burke, I.G. (2009) Advances in improving the quality and flexibility of compound management. J. Biomol. Screen., 14 (5), 444–451.
3. ANSI (2004) New Microplate Standards Expected to Accelerate and Streamline Industry, ANSI, New York, http://www.ansi.org/news_publications/news_story.aspx?menuid=7&articleid=598 (accessed 2004). ANSI/SBS 1-2004: Footprint Dimensions ANSI/SBS, 2-2004: Height Dimensions ANSI/SBS, 3-2004: Bottom Outside Flange Dimensions ANSI/SBS 4-2004: Well.
4. Warr, W.A. (1991) Some observations on piecemeal electronic publishing solutions in the pharmaceutical industry. J. Chem. Inf. Comput. Sci., 31 (2), 181–186.
5. Oprea, T.I. (2000) Property distribution of drug-related chemical databases. J. Comput. Aided Mol. Des., 14 (3), 251–264.
6. Rutherford, M.L. and Stinger, T. (2001) Recent trends in laboratory automation in the pharmaceutical industry. Curr. Opin. Drug Discov. Devel., 4 (3), 343–346.
7. Ray, B.J. (2001) Value your compound management team! Drug Discov. Today., 6 (11), 563.
8. Janzen, W.P. (2002) High Throughput Screening: Methods and Protocols, Humana Press, Totowa, NJ.
9. Eiseman, E. and Haga, S. (1999) Handbook of Human Tissue Sources: A National Resource of Human Tissue Samples, Rand Corporation.
10. Ari, N., Westling, L., and Isbell, J. (2006) Cherry-picking in an orchard: unattended LC/MS analysis from an autosampler with >32,000 samples online. J. Biomol. Screen., 11 (3), 318–322.
11. Letot, E., Koch, G., Falchetto, R., Bovermann, G., Oberer, L., and Roth, H.J. (2005) Quality control in combinatorial chemistry: determinations of amounts and comparison of the ‘purity’ of LC-MS-purified samples by NMR, LC-UV and CLND. J. Comb. Chem., 7 (3), 364–371.
12. Popa-Burke, I.G., Issakova, O., Arroway, J.D., Bernasconi, P., Chen, M., Coudurier, L. et al. (2004) Streamlined system for purifying and quantifying a diverse library of compounds and the effect of compound concentration measurements on the accurate interpretation of biological assay results. Anal. Chem., 76 (24), 7278–7287.
13. Kozikowski, B.A., Burt, T.M., Tirey, D.A., Williams, L.E., Kuzmak, B.R., Stanton, D.T. et al. (2003) The effect of freeze/thaw cycles on the stability of compounds in DMSO. J. Biomol. Screen., 8 (2), 210–215.
14. Kozikowski, B.A., Burt, T.M., Tirey, D.A., Williams, L.E., Kuzmak, B.R., Stanton, D.T. et al. (2003) The effect of room-temperature storage on the stability of compounds in DMSO. J. Biomol. Screen., 8 (2), 205–209.
15. Rasmussen, D.H. and Mackenzie, A.P. (1968) Phase diagram for the system water-dimethylsulphoxide. Nature, 220 (5174), 1315–1317.
16. Schopfer, U., Engeloch, C., Stanek, J., Girod, M., Schuffenhauer, A., Jacoby, E. et al. (2005) The Novartis compound archive – from concept to reality. Comb. Chem. High Throughput Screen., 8 (6), 513–519.
17. Jacoby, E., Schuffenhauer, A., Popov, M., Azzaoui, K., Havill, B., Schopfer, U. et al. (2005) Key aspects of the Novartis compound collection enhancement project for the compilation of a comprehensive chemogenomics drug discovery screening collection. Curr. Top. Med. Chem., 5 (4), 397–411.
18. Engeloch, C., Schopfer, U., Muckenschnabel, I., Le Goff, F., Mees, H., Boesch, K. et al. (2008) Stability of screening compounds in wet DMSO. J. Biomol. Screen., 13 (10), 999–1006.
19. Palmer, R.C. (1995) The Bar Code Book: Reading, Printing, Specification, and Application of Bar Code and Other Machine Readable Symbols, 3rd edn, Helmers Publishing Inc., Peterborough, NH.
20. Burke, H.E. (1990) Automating Management Information Systems, Van Nostrand Reinhold, New York.
2
Generating a High-Quality Compound Collection
Philip B. Cox and Anil Vasudevan
2.1 Defining Current Screening Collections
In part due to sustained effort aimed at adding drug-like compounds via internal/external synthesis but also complemented with mergers and acquisitions, most corporate collections comprise upwards of several hundred thousand compounds. Improvements in automation, miniaturization, and novel assay technologies have enabled ultra-high-throughput screening (uHTS) (>100 000 compounds per day) to become a routine strategy for hit identification. A recent analysis indicated that 104 compound candidates progressed into clinical studies from hits identified through uHTS prior to 2004, and 4 of these molecules are currently represented in approved drugs [1]. However, as the complexity of targets (or the confidence in them) evolves, uHTS is not always desirable due to cost effectiveness and other practical consideration, as discussed in Chapter 13. We provide our corroborative perspective on carefully selecting a screening set below.
The two commonly adopted approaches to match objective with screening effort are known as the focused and diversity methods of compound selection. Underlying both these methods is the ‘similarity property principle’ [2], which states that high-ranked structures are likely to have similar activity to that of the reference structure. Focused methods use this principle to try to find compounds that exhibit similar biological activity to a reference molecule or pharmacophore already known to be active. Diverse selection methods use the principle of choosing evenly across chemical space, hence maximizing the odds of finding diverse compounds. There are many methods used to assemble a diverse subset of molecules from a larger population for screening, a few of which are cluster-based selection [3], partition-based [4], or maximum dissimilarity [5]. Regardless of which screening philosophy is pursued, when the objective is to initiate a hit-to-lead effort, the most important outcome of any high throughput screening (HTS) campaign (or fast-follower approach) is the chemotype hit rate, distinct from the overall HTS hit rate [6].
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