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Chemical, target, and bioactive properties of allosteric modulation.

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.

SUBMITTER: van Westen GJ

PROVIDER: S-EPMC3974644 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Chemical, target, and bioactive properties of allosteric modulation.

van Westen Gerard J P GJ Gaulton Anna A Overington John P JP

PLoS computational biology 20140403 4

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 ...[more]

PMID: 24699297

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Project description:The prediction of biological targets of bioactive molecules from machine-readable materials can be routinely performed by computational target prediction tools (CTPTs). However, the prediction of biological targets of bioactive molecules from non-digital materials (e.g., printed or handwritten documents) has not been possible due to the complex nature of bioactive molecules and impossibility of employing computations. Improving the target prediction accuracy is the most important challenge for computational target prediction. A minimum structure is identified for each group of neighbor molecules in the proposed method. Each group of neighbor molecules represents a distinct structural class of molecules with the same function in relation to the target. The minimum structure is employed as a query to search for molecules that perfectly satisfy the minimum structure of what is guessed crucial for the targeted activity. The proposed method is based on chemical similarity, but only molecules that perfectly satisfy the minimum structure are considered. Structurally related bioactive molecules found with the same minimum structure were considered as neighbor molecules of the query molecule. The known target of the neighbor molecule is used as a reference for predicting the target of the neighbor molecule with an unknown target. A lot of information is needed to identify the minimum structure, because it is necessary to know which part(s) of the bioactive molecule determines the precise target or targets responsible for the observed phenotype. Therefore, the predicted target based on the minimum structure without employing the statistical significance is considered as a reliable prediction. Since only molecules that perfectly (and not partly) satisfy the minimum structure are considered, the minimum structure can be used without similarity calculations in non-digital materials and with similarity calculations (perfect similarity) in machine-readable materials. Nine tools (PASS online, PPB, SEA, TargetHunter, PharmMapper, ChemProt, HitPick, SuperPred, and SPiDER), which can be used for computational target prediction, are compared with the proposed method for 550 target predictions. The proposed method, SEA, PPB, and PASS online, showed the best quality and quantity for the accurate predictions.

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Chemical, target, and bioactive properties of allosteric modulation.

Publications

Chemical, target, and bioactive properties of allosteric modulation.

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