metabolite databasing - lest we forget 2011-09-12آ  databasing –lest we forget. turning...

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  • Metabolite Spectral

    Databasing – Lest we

    forget.

    Turning structural data into

    knowledge

    Steve Thomas GSK

    European User Meeting

    15th June 2011

  • Ware R&D

    1300 staff

    Pre-Clinical Development

    R&D PTS BDD SID

    Structural

    Identification

  • Drug metabolism safety cover

    Human

    Rat

    Dog

  • Safety implications

    The implications of passing a unsafe

    drug into the clinic are severe.

    Getting it wrong is not an option.

    What’s on our side?

    •Top end equipment

    •Experience

    •Historical data

    •Ability to smell a structural alert

    from 20 yards!

  • Historical data storage

  • A good memory

    Grand wizard of

    metabolism – Frank Hollis

    GSK employee:

    Late Jurassic - Feb 2009

    Contingency plan on Frank’s

    retirement!

    http://2.bp.blogspot.com/_4g3iqvrNSZw/RsViderVkwI/AAAAAAAAAAM/Q_9UQsBo7UI/s1600-h/brain-in-a-vat.jpg

  • US usage of ACD

    O

    O O

    OH O

    H

    •Early adoption from v7 in 2005 to v12 currently

    •UK usage in MDR and ChemDev

    ON

    O

    N

    N

    N

    O

    Cl

    O

    Cl CH3 H

    N +

    O

    O -

    O

    NH

    NH

    N

    S

    CH3 CH3

    CH3

    NH

    OH

    OH

    OH

    CH3 CH3

    CH3

  • Drill down from a biotransformation map

  • Search data from any point of interest

    Variety of

    customers leads

    to a wide range

    of ideas as to

    which data is

    most important.

    http://www.google.co.uk/imgres?imgurl=http://www.rotaryfirst100.org/philosophy/images/scientist.gif&imgrefurl=http://www.rotaryfirst100.org/philosophy/scientists/index.htm&usg=__UwdQUPyv44dD5q4S4R5sP4Qd6hM=&h=365&w=418&sz=13&hl=en&start=13&um=1&itbs=1&tbnid=KDQcVw5x6PrT6M:&tbnh=109&tbnw=125&prev=/images?q=scientist&um=1&hl=en&sa=N&ndsp=20&tbs=isch:1

  • Chemfolder Enterprise

    A B C D+ +

    Initially designed as a tool for synthetic chemists:

    – CFE allows users to database reactions

    – Links to data supporting structure assignments

    – Structures searchable

    –“Has this been made before?”

    – Data searchable

    –“What have I made?”

    To be of use in metabolism, the system must cope with 50+ products?

  • User data entry form

    Auto triggered on

    update.

    Fully customisable

    •Free text

    •Auto fill e.g. Date

    •Combiboxes

    •Radio (choice)

    •Mandatory entry

  • ChemFolder – Biotransformation Map

  • ChemFolder – Biotransformation Map

  • Stitching databases together.

  • Populating the map

  • Screen space and unknowns

    Enzyme: CYP3A4

  • The database grows..

    On data load, CFE

    retrieves every

    spectrum for every

    link for every

    metabolite.

    Over 100

    metabolites:

    most with at least two

    spectra, some up to

    10!

  • Flexible reporting

    Interpretation sheet

    possible

    Fragments properly

    represented

    Structures editable

    Exportable

  • The database grows..

  • Future? Biotrans map comparison

    1/3

    Human

  • Data dependant display

  • Summary

    Current LinkID approach functional and useful

    – Planned to become single entity

    Valuable way to store, search and share sets of related molecules

    – Body (metabolites)

    – Environment (stability)

    – Chemist (reactions / impurities)

    Further enhancements constantly delivered

    – Searchable assignments from within CFE

  • Acknowledgements

    Ian Peirson

    Paul Hubberstey

    All of SID-Ware

    Frank’s brain

    http://2.bp.blogspot.com/_4g3iqvrNSZw/RsViderVkwI/AAAAAAAAAAM/Q_9UQsBo7UI/s1600-h/brain-in-a-vat.jpg