Due to the emergence of new diseases, unmet medical needs or orphan diseases, as well as the reduced efficacy of certain therapeutic agents, there is an urgent need for new drugs that act on new targets and/or via new mechanisms. Proteins can adopt several macroscopically distinguishable conformations, the populations of which are governed by their intrinsic structural stability and the interaction of different biological effectors (cofactors, activators and inhibitors, interactors) and environmental variables, giving rise to macromolecular ensembles in which certain conformational states may be physiologically and/or pathologically relevant. This is particularly relevant in the case of intrinsically or conditionally disordered proteins. Transient, non-native and inactive alternative conformational states may be the target of drugs that stabilize these states and prevent conversion to functional active states in an allosteric manner, thereby blocking the activity of disease-related dysregulated proteins.
We will review some examples of our work on the identification and development of allosteric inhibitors that exploit the conformational heterogeneity of target proteins.
