Polypharmacology of multiple GPCR targets
The client’s project was investigating poly-pharmacology effects of a combination of antagonism at two or more Class A GPCRs. MedChemica examined the data from the literature and patents, performing both matched molecular pair analysis (MMPA), and model building to predict potency, based on random forest modelling of the unique fragments generated by the MMPA. Using the analysis key groups were identified where potency was gained at the GPCR targets, and critically where changes could be made. MCPairs Compounds-From-Rules generated ideas, and with further ideas from project medicinal chemists, were tested in-silico with the potency prediction models. Reduction to practice by the synthesis of these molecules generated novel compounds, and actives, to test in-vivo for the desired pharmacology. The diagram above illustrates the process and plots where key side chains were highlighted.