Determination of thermodynamic parameters ΔG and ΔH of a small molecule binding to p38 using MST

In current drug discovery efforts, hits arediscovered by conventional high-throughput or fragment screening campaigns. Hits derived from these screening campaigns belong to various chemical scaffolds. These ones, or the winners are then progressed through extensive anditerative lead optimization cycles, that aim at improving the affinity towards the target, selectivity alongside physicochemical DMPK and ADME properties. According to Ferenczy et al. (2010) a large portionof the unfavorable properties of leads results fromthe optimization process itself, especially through increasing affintiy by adding lipophilicity. This is true for HTS and fragment hits, where the current medicinal chemistry practice drives the candidate molecules to the edge of the Lipinski zone. It seems to be much more straight forward to increase lipophilicity and complexity of leads in an entropy-driven optimization than improve specific interactions that result in an enthalpy-driven optimization. Therefore Ferenczy et al. suggest a guideline that monitors the binding free energy early on in the drug discovery process, and use this information for the ranking of compoundseries.