Abstract Details

Poster 50: Commercial Fragment Coverage of Exemplified Medicinal Chemistry Substructures from ChEMBL

Yi Mok1,2, Ruth Brenk2,3, Nathan Brown1
1Cancer Research UK Cancer Therapeutics Unit, Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Belmont, London SM2 5NG, U.K.
2Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, U.K.
3Johannes Gutenberg-Universität Mainz, Institut für Pharmazie und Biochemie, Staudinger Weg 5, 55128 Mainz, Germany
The application of fragment screening has become an increasingly important technique in early stage drug discovery. Fragments occupy the chemical space that is commonly described by the ‘rule-of-three’ (Ro3) criteria of physicochemical properties,[1] where the compounds are smaller than those from conventional high-throughput screening (HTS). The screening of fragment-sized molecules enables a greater coverage of chemical diversity using a smaller collection of compounds. As a result, it becomes more affordable for academia and biotech companies to apply fragment screening than conventional HTS involving millions of screening compounds.

Many fragment screening libraries contain compounds originated either from commercial sources or proprietary synthetic chemical intermediates. To ensure sufficient sampling of chemical space in fragment screening, it is important to understand the current coverage of known medicinal chemistry space using commercial fragments. Using ChEMBL as an open-access medicinal chemistry repository, this study investigated the overlap between the chemical space of exemplified medicinal chemistry substructures generated from ChEMBL and that of fragments available from commercial vendors. Molecular substructures were obtained using ring segmentation[2] and Level 1 scaffolds.[3] All resultant substructures from ChEMBL molecules satisfying the Ro3 criteria were then compared to Ro3-compliant commercial fragments.

Results from both substructure generation methods agreed well. Only 40% of the ring segments and 35% of the Level 1 scaffolds in Ro3-compliant ChEMBL substructures were represented by commercial fragments. The majority of ChEMBL substructures not covered by commercial fragments was characterised by high molecular weights and high proportion of saturation. More surprisingly, 60% of the ring segments and 50% of the Level 1 scaffolds in Ro3-compliant commercial fragments were not exemplified in any ChEMBL molecules. Again, the overlap decreased upon increasing molecular complexity of the ring segments and scaffolds. These unshared commercial fragments might have limited medicinal chemistry value, thus have not been represented in ChEMBL molecules. However, we speculate that these fragments have been conventionally disfavoured for the reason of synthetic attractiveness.

Attempts to trace the synthetic origins of the parent ChEMBL molecules of non-represented ChEMBL substructures will be discussed. The properties of ChEMBL substructures appeared only in bioactive molecules (defined as compounds having Ki, Kd IC50 or EC50 <= 10 uM) will also be reported.

While there is an increasing awareness in the community to enhance the complexity of fragment molecules, for instance using diversity-oriented synthesis and natural-product-derived fragments,[4,5] the results here highlight that the diversity of Ro3-compliant commercial fragments should not be overlooked for the purpose of expanding the chemical space sampling in fragment screening.

[1] Congreve et al. (2003) A rule of three for fragment-based lead discovery? Drug Discov. Today, 8, 876-877.
[2] Brenk et al. (2008) Lessons learnt from assembling screening libraries for drug discovery for neglected diseases. ChemMedChem, 3, 435-444.
[3] Langdon et al. (2011) Scaffold diversity of exemplified medicinal chemistry space. J. Chem. Inf. Model., 51, 2174-2185.
[4] Hung et al. (2011) Route to three-dimensional fragments using diversity-oriented synthesis. Proc. Natl. Acad. Sci. U.S.A., 108, 6799-6804.
[5] Over et al. (2013) Natural-product-derived fragments for fragment-based ligand discovery. Nature Chem., 5, 21-28.

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