Annotation of Allosteric Compounds to Enhance Bioactivity Modeling for Class A GPCRs

[Image: see text] 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.