Data Management for Combinatorial Chemistry

Maryjo Zaborowski
Chiron Corporation
4560 Horton Street
Emeryville, CA 94608 USA
Tel: +1-510-601-3542

Sheila H. DeWitt
Parke-Davis Pharmaceutical Research
Division of Warner-Lambert Company
2800 Plymouth Road
Ann Arbor, Michigan 48105 USA



http://www.netsci.org/Science/Combichem/feature13.html

Introduction

Combinatorial chemistry and high throughput synthesis techniques have done more than change the field of chemistry as applied to drug discovery. These new synthetic technologies have introduced dramatically different chemical and biological information-handling requirements. With the advent of combinatorial chemistry and high throughput synthesis, many companies are now reporting 10- to 50-fold increases in the number of compounds made and tested annually. At most companies, existing information technology and business operations, such as compound registration practices and assay result visualization, cannot accommodate this increase.

In order to gauge the current use of combinatorial techniques and the information systems which manage results from these efforts, a questionnaire was distributed to chemical information specialists from several companies. Replies were received from seventeen companies which ranged from small biotechnology groups to multi-national pharmaceutical companies. The questionnaire and results are provide and the results are summarized.

Experience and Direction - Status of Synthetic Effort

While there has been a significant amount writen about combinatorial approaches to chemistry, the area is still very immature. Of the companies surveyed, only three reported "long-standing" combinatorial synthesis and/or high throughput synthesis programs (> 2 years). Six companies reported medium-length (1-2 years) programs. Four companies reported young programs (6 months - 1 year). The remaining companies were initiating programs and/or purchasing libraries from outside sources. Of the three companies with >2 years experience, two companies practice combinatorial synthesis only. The third company emphasizes combinatorial mixtures but also pursues high throughput synthesis.

Combinatorial chemistry is not used exclusively for lead generation. Each company with established groups reported programs in both chemistry and high throughput synthesis, although larger resources were reported to be allocated to combinatorial chemistry. Companies with less than a year of experience reported emphasis on high throughput synthesis.

Synthesis Emphasis - Types of Chemistry(s) Employed

Seven companies reported the use of solid phase organic synthesis (SPOS) for novel, non-oligomeric compounds. Most of these companies reported a library inventory of 50-100 combinatorial libraries (non-deconvolution mixtures).

Nine companies reported exclusive use of solution phase chemistry. Seven (including some of the above category) indicated some creation of peptoid and/or peptide libraries.

Number of Compounds per Mixture

Six companies routinely prepare mixtures of >100 compounds/pool. Each of these companies also reported the use of SPOS chemistry. Three of these companies reported having combinatorial efforts exclusively. Five companies reported the routine preparation of mixtures of 10-100 compounds/pool. Two companies routinely prepare mixtures of 1-10 compounds pool.

Information Systems/Access to Data

All companies reported having traditional chemical registration systems for registering discrete compounds. However, only six companies reported having an information system for the registration and storage of combinatorial chemistry products. Of those six, three reported having Library Design software. An interesting point to come out of this survey was that only five companies claimed to be using combinatorial chemistry assay data effectively.

Ten companies reported using relational databases (e.g. Oracle) to store assay results and related library information. Six companies reported no central storage of assay data; information is saved in Excel. One company stated that they use their chemistry software to store assay data.

Tracking the synthesis, testing and heritage of deconvolution products was reported as the second most pressing information problem after registration. This answer was common to companies with >1 year experience with combinatorial chemistry and companies with combinatorial chemistry information systems.

Company Information

1. Company Classification 

    2:  Biotech
   14:  Pharmaceutical
    1:  Chemical

2. Synthesis Direction

    5:  Combinatorial mixtures only
    0:  High throughput synthesis only
    6:  Emphasis on combinatorial mixtures, but high
         throughput synthesis is pursued.
    5:  Emphasis on high throughput synthesis, but 
         combinatorial mixtures are pursued.

3. Purpose of Combinatorial Chemistry Effort

    7:  Lead generation
    2:  Lead optimization
    8:  Combinatorial mixtures for lead generation and high 
         throughput synthesis for lead optimization.

4. Emphasis of Synthetic Efforts

    9:  Use of known solution phase chemistry
    7:  Use of solid phase chemistry (e.g. peptides, 
         peptoids)
    7:  Development of solid phase organic synthesis (SPOS) 
         for novel, non-oligomeric compounds

5. Location of Efforts

   10:  Central laboratory
    8:  Decentralized throughout chemistry group

6. Status of Synthesis Effort

    3:  Not yet operational
    4:  1 year
    6:  1-2 years
    3:  >2 years

7. Total Number of Combinatorial Mixtures Generated to Date

    3:  0
    2:  1-10
    3:  10-100
    8:  >100

8. Total Number of Compounds in EACH Combinatorial Mixture

    2:  1-10
    5:  10-100
    6:  >100

9. Total Number of Discrete Compounds (generated to date by high throughput or parallel synthesis methods)

    2:  0
    4:  1-100
    4:  100-1000
    6:  >1000

10. Combinatorial Chemistry Project Composition

    5:  Stand-alone group, chemists only - one supervisor
    1:  Stand-along group, multi-disciplinary (includes, for example,
          chemists, modelers, engineers) - one supervisor
    0:  Collaborative effort, chemists only - multiple supervisors
    3:  Collaborative effort, multi-disciplinary BUT dedicated to the 
          effort - multiple supervisors
    7:  Collaborative effort, multi-disciplinary BUT each pat is NOT 
          solely dedicated to the effort - multiple supervisors.

Combinatorial Chemistry System Development

11. Information System Presently in Place

    4:  None
    6:  Chemical planning and synthesis
   11:  Structure registration
   10:  Data registration
    5:  Library design
    3:  Deconvolution of mixtures
    9:  Assay result storage

12. Accessibility of Information

    2:  Local, not shared among labs
    2:  Local, shared via central system
   11:  Central, host-based

13. Vision for Compound Registration System

    7:  Separate systems for combinatorial chemistry and traditional
          chemistry
    9:  Central system for both combinatorial and traditional 
          chemistries

14. Where are Assay Results Stored?

    1:  Within registration system
    6:  Within desktop programs (e.g. Excel)
   10:  Within relational databases on host

15. Primary Users of Current System

   14:  Chemists
    2:  Information scientists
    5:  Biologists

16. Development Philosophy

    6:  Utilize vendor system
    3:  Internal development - best solution for competitive advantage
    6:  Internal development - needs not met by vendor systems

17. Development of Information System Driven By:

    1:  Registration group
    8:  Chemists
    0:  Modeling group
    2:  Programming group

18. Preferred System Architecture

    1:  Single system - single interface
    8:  Multiple systems - single interface
    3:  Multiple systems - multiple interfaces

19. Individuals Involved in Systems Development for Combinatorial Chemistry

    6:  0
    8:  1-5
    1:  5-10
    1:  >10

20. Have You Investigated Multiple Vendor Registration Systems?

    5:  Yes
   10:  No

21. Which ones?

    MDL, Daylight, Tripos, Chemical Design

22. Have You Investigated Multiple Vendor Systems for Library Design, Assay Result Handling, etc?

    1:  Yes
   11:  No

23. Important Features of Vendor Systems

   10:  Flexibility
    7:  Customization potential
    5:  Most built-in features
    4:  No internal development or support needed

Information Handling Issues

24. Most Pressing Concerns

   10:  Registration of large numbers of compounds
    8:  Tracking and deconvolution of mixtures
    8:  Association of assay results with mixtures
    5:  Association of assay results with discrete compounds
    1:  Reduction of raw assay data
    2:  User compliance

25. Is Your Combinatorial Chemistry Data Used Effectively?

    5:  Yes
    7:  No

26. Which Tools Are/Would Be Most Useful?

    Cluster/trend analysis
    +/- hit discrimination
    Electronic notebook

27. Storage of Negative Data

   13:  Useful
    1:  Not useful

28. Accuracy of Negative Data from Combinatorial Chemistry Testing

    1:  Assume full accuracy
   11:  Assume some "likelihood"
    1:  Assume no accuracy

Information Technology Staff

29. With the changing synthetic technology and improving information technology, is the skill requirement for IT people increasing dramatically?

    4:  Yes
    7:  Probably
    4:  No

30. What skills are necessary for IT personnel to support a combinatorial chemistry/high throughput synthesis effort?

    Chemistry and computers, mathematics, statistics, C
    programming, Oracle database management, knowledge of coming 
    information technology

31. Desired skills

    client-server tools


NetSci, ISSN 1092-7360, is published by Network Science Corporation. Except where expressly stated, content at this site is copyright (© 1995 - 2010) by Network Science Corporation and is for your personal use only. No redistribution is allowed without written permission from Network Science Corporation. This web site is managed by:

Network Science Corporation
4411 Connecticut Avenue NW, STE 514
Washington, DC 20008
Tel: (828) 817-9811
E-mail: TheEditors@netsci.org
Website Hosted by Total Choice