Abstract
Allosteric modulators are ligands for proteins that exert their effects via a different binding site than the natural (orthosteric) ligand site and hence form a conceptually distinct class of ligands for a target of interest. Here, the physicochemical and structural features of a large set of allosteric and non-allosteric ligands from the ChEMBL database of bioactive molecules are analyzed. In general allosteric modulators are relatively smaller, more lipophilic and more rigid compounds, though large differences exist between different targets and target classes. Furthermore, there are differences in the distribution of targets that bind these allosteric modulators. Allosteric modulators are over-represented in membrane receptors, ligand-gated ion channels and nuclear receptor targets, but are underrepresented in enzymes (primarily proteases and kinases). Moreover, allosteric modulators tend to bind to their targets with a slightly lower potency (5.96 log units versus 6.66 log units, p<0.01). However, this lower absolute affinity is compensated by their lower molecular weight and more lipophilic nature, leading to similar binding efficiency and surface efficiency indices. Subsequently a series of classifier models are trained, initially target class independent models followed by finer-grained target (architecture/functional class) based models using the target hierarchy of the ChEMBL database. Applications of these insights include the selection of likely allosteric modulators from existing compound collections, the design of novel chemical libraries biased towards allosteric regulators and the selection of targets potentially likely to yield allosteric modulators on screening. All data sets used in the paper are available for download.
Highlights
Allosteric modulators The generation of drug-like lead and candidate molecules against a specific molecular target remains a major challenge in drug discovery
The authors feel that other potential applications could be the following: Firstly, creation of allosteric focused libraries based on known chemical properties of allosteric modulators, these libraries can be further sub divided on target type (e.g. Class A GPCR or Protein Kinase)
As stated in the introduction, the term allosteric modulator is a very broad definition directly depending on the target in question
Summary
Allosteric modulators The generation of drug-like lead and candidate molecules against a specific molecular target remains a major challenge in drug discovery. While some papers have previously been published classifying allosteric modulators as a separate class of ligands in general, here it is argued that the physicochemical properties of the molecules depend on the target in question [11,18]. In the case of proteins with multiple functions and active sites, categorizing ligands as allosteric versus orthosteric can be problematic. Several inhibitors are known to inhibit the protein via the ATP binding site (which is commonly referred to as orthosteric inhibition, type I inhibition).
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