Compounds in the bRo5 chemical space are suited for modulation of targets that have large, flat or groove-shaped binding sites, for instance protein–protein interactions (PPIs). A molecular chameleon is a compound that can adapt its conformation to the environment. It is a flexible structure which can form intramolecular interactions, including intramolecular hydrogen bonds (IMHBs). Chameleonic properties are relevant in the bRo5 chemical space since they can mask undesired polar groups that can limit permeability and thus bioavailability of drug candidates. To obtain efficient and reliable QSPR methods for the prediction of solubility and cell permeability of bRo5 compounds, chameleonicity should therefore be considered. In the first part of the talk I am showing some strategies a) to identify the conformers responsible for the chameleonic behavior (i.e. conformers present in the aqueous and membrane interior-like environments) and b) to build QSPR models of cell permeability and solubility based on ad hoc descriptors calculated from the conformations governing chameleonic properties. In the second part of the talk I am discussing how dynamic IMHBs deserve to be included in medicinal chemistry projects to augment traditional strategies for optimization of bRo5 leads. For instance, the transformation of a natural product into a molecular chameleon through the introduction of appropriately positioned HBD/HBA groups, may provide compounds in which high solubility and cell permeability are combined with potent target binding in a very effective manner. Overall this presentation supports that controlling the chameleonic properties of bRo5 compounds could allow researchers to discover new drugs for difficult-to-drug-targets that cannot be modulated with Ro5 compliant small molecules and are inaccessible to biologics. Moreover, a good ability to handle molecular chameleons could fully release the potential of cyclic peptides and macrocycles in drug discovery.

Rationally controlling the chameleonic properties of beyond Rule of 5 (bRo5) compounds

2019 Fall National Meeting

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