期刊
CHEMMEDCHEM
卷 13, 期 6, 页码 540-554出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201700561
关键词
computer chemistry; generative topographic mapping; library comparison; molecular diversity; structure analysis
资金
- European Union's Horizon research and innovation program under the Marie Sklodowska-Curie grant [676434]
This is, to our knowledge, the most comprehensive analysis to date based on generative topographic mapping (GTM) of fragment-like chemical space (40 million molecules with no more than 17 heavy atoms, both from the theoretically enumerated GDB-17 and real-world PubChem/ChEMBL databases). The challenge was to prove that a robust map of fragment-like chemical space can actually be built, in spite of a limited (<<10(5)) maximal number of compounds (frame set) usable for fitting the GTM manifold. An evolutionary map building strategy has been updated with a coverage check step, which discards manifolds failing to accommodate compounds outside the frame set. The evolved map has a good propensity to separate actives from inactives for more than 20 external structure-activity sets. It was proven to properly accommodate the entire collection of 40m compounds. Next, it served as a library comparison tool to highlight biases of real-world molecules (PubChem and ChEMBL) versus the universe of all possible species represented by FDB-17, a fragment-like subset of GDB-17 containing 10 million molecules. Specific patterns, proper to some libraries and absent from others (diversity holes), were highlighted.
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