Abstract Details

Poster 36: Beating (the) Competition in Lead Discovery; Property and Structural trends in Allosteric Regulators

Gerard JP van Westen1, Anna Gaulton1, John P Overington1
We analyze the physicochemical and structural features of a large set of allosteric and non-allosteric ligands from the ChEMBL database of bioactive molecules. We find that there are differences in chemical features. Among other things allosteric modulators are smaller, more lipophilic and more rigid compounds. Furthermore, there are differences in the target distribution. Allosteric modulators are overrepresented in membrane receptors, ligand gated ion channels, and nuclear receptors; but are underrepresented in proteases and kinases. Moreover, allosteric modulators tend to bind to their targets with a lower potency (5.89 log units versus 6.85 log units, p < 0.05). However, this lower absolute affinity difference is compensated for by their smaller lipophilic nature leading to a similar binding efficiency index and surface efficiency index. We then develop a series of classifier models, using the target hierarchy of the ChEMBL database to build target class independent models, and finer-grained target architecture/functional class classifications. Applications of these insights include the selection of likely allosteric modulators from extant compound collections/catalogues, the design of novel chemical libraries biased towards containing the features of allosteric regulators and recommendations to optimize assays for allosteric modulator identification.

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