Chemical, Target, and Bioactive Properties of Allosteric Modulation

• DOI: 10.1371/journal.pcbi.1003559
• Publication Date: 2014-04-03T20:29:23Z
• Authors: Gerard J. P. van ...; Anna Gaulton; John P. Overington
• Keywords: chEMBL; Allosteric enzyme

Allosteric modulators are ligands for proteins that exert their effects via a different binding site than the natural (orthosteric) ligand and hence form conceptually distinct class of target interest. Here, physicochemical structural features large set allosteric non-allosteric from ChEMBL database bioactive molecules analyzed. In general relatively smaller, more lipophilic rigid compounds, though differences exist between targets classes. Furthermore, there in distribution bind these modulators. over-represented membrane receptors, ligand-gated ion channels nuclear receptor targets, but underrepresented enzymes (primarily proteases kinases). Moreover, tend to with slightly lower potency (5.96 log units versus 6.66 units, p<0.01). However, this absolute affinity is compensated by molecular weight nature, leading similar efficiency surface indices. Subsequently series classifier models trained, initially independent followed finer-grained (architecture/functional class) based using hierarchy database. Applications insights include selection likely existing compound collections, design novel chemical libraries biased towards regulators potentially yield on screening. All data sets used paper available download.