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Positive allosteric modulators to peptide GPCRs: a promising class of drugs.

ABSTRACT: The task of finding selective and stable peptide receptor agonists with low molecular weight, desirable pharmacokinetic properties and penetrable to the blood-brain barrier has proven too difficult for many highly coveted drug targets, including receptors for endothelin, vasoactive intestinal peptide and galanin. These receptors and ligand-gated ion channels activated by structurally simple agonists such as glutamate, glycine and GABA present such a narrow chemical space that the design of subtype-selective molecules capable of distinguishing a dozen of glutamate and GABA receptor subtypes and possessing desirable pharmacokinetic properties has also been problematic. In contrast, the pharmaceutical industry demonstrates a remarkable success in developing 1,4-benzodiazepines, positive allosteric modulators (PMAs) of the GABAA receptor. They were synthesized over 50 years ago and discovered to have anxiolytic potential through an in vivo assay. As exemplified by Librium, Valium and Dormicum, these allosteric ligands of the receptor became the world's first blockbuster drugs. Through molecular manipulation over the past 2 decades, including mutations and knockouts of the endogenous ligands or their receptors, and by in-depth physiological and pharmacological studies, more peptide and glutamate receptors have become well-validated drug targets for which an agonist is sought. In such cases, the pursuit for PAMs has also intensified, and a working paradigm to identify drug candidates that are designed as PAMs has emerged. This review, which focuses on the general principles of finding PAMs of peptide receptors in the 21st century, describes the workflow and some of its resulting compounds such as PAMs of galanin receptor 2 that act as potent anticonvulsant agents.

SUBMITTER: Bartfai T

PROVIDER: S-EPMC4002610 | biostudies-other | 2013 Jul

REPOSITORIES: biostudies-other

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Project description:Proteins often have both orthosteric and allosteric binding sites. Endogenous ligands, such as hormones and neurotransmitters, bind to the orthosteric site, while synthetic ligands may bind to orthosteric or allosteric sites, which has become a focal point in drug discovery. Usually, such allosteric modulators bind to a protein noncompetitively with its endogenous ligand or substrate. The growing interest in allosteric modulators has resulted in a substantial increase of these entities and their features such as binding data in chemical libraries and databases. Although this data surge fuels research focused on allosteric modulators, binding data is unfortunately not always clearly indicated as being allosteric or orthosteric. Therefore, allosteric binding data is difficult to retrieve from databases that contain a mixture of allosteric and orthosteric compounds. This decreases model performance when statistical methods, such as machine learning models, are applied. In previous work we generated an allosteric data subset of ChEMBL release 14. In the current study an improved text mining approach is used to retrieve the allosteric and orthosteric binding types from the literature in ChEMBL release 22. Moreover, convolutional deep neural networks were constructed to predict the binding types of compounds for class A G protein-coupled receptors (GPCRs). Temporal split validation showed the model predictiveness with Matthews correlation coefficient (MCC) = 0.54, sensitivity allosteric = 0.54, and sensitivity orthosteric = 0.94. Finally, this study shows that the inclusion of accurate binding types increases binding predictions by including them as descriptor (MCC = 0.27 improved to MCC = 0.34; validated for class A GPCRs, trained on all GPCRs). Although the focus of this study is mainly on class A GPCRs, binding types for all protein classes in ChEMBL were obtained and explored. The data set is included as a supplement to this study, allowing the reader to select the compounds and binding types of interest.

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Positive allosteric modulators to peptide GPCRs: a promising class of drugs.

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