GPCR-tailored pharmacophore pattern recognition of small molecular ligands

The goal of our work was to differentiate between patterns, which are responsible for the activity of small molecular ligands binding to G-protein coupled receptors (GPCRs) and molecules, which are pharmacologically active on other target classes. Second the aim was to go one step further and analyze the chemical space occupied by GPCR active ligands itself, to distinguish between the actives of different subclasses or even cluster ligands for single receptors. To achieve these objectives, we have built a database of small, organic molecules, which bind to GPCRs. Once this crucial foundation for pattern recognition has been laid, we needed to find a descriptor, which is able to detect the compulsory features responsible for activity within a molecule. In this matter we found that the well accepted pharmacophore descriptor served us well. Finally we needed to find a method to display the clustering or separation of the specific ligands. We found that self-organizing maps (SOMs) perform excellently in this task. We herein present the analysis of the chemical space of active compounds, depending on their biological target, the GPCRs. We will also discuss the techniques used to create the chemical spaces. The findings can be applied and have an impact at various stages of the drug discovery process.