Molecules that are “Beyond the Rule-of-Five” (Bro5) can be promising drug candidates or chemical tools. BRo5 molecules have larger binding surfaces and can provide superior potency and selectivity when compared to small molecule drugs. Unfortunately, BRo5 compounds are most frequently unable to cross cell membranes, limiting their access to intracellular targets and preventing their potential oral bioavailability. Recent studies of BRo5 molecules show cell permeability is still possible but molecules must conform to a stringent set of physical property rules. In particular, the number of hydrogen bond donors must be restricted if these molecules are to permeate cell membranes and reach targets.
A number of approaches have been developed to reduce the hydrogen bond donors present in BRo5 molecules; notably N-methylation of peptide amides or replacement of donors with bioisosteres. Unfortunately, these strategies often reduce or abolish target binding because the hydrogen bond donors are essential for binding interactions. This dilemma of wanting hydrogen bond donors for target binding, but wanting to remove them for cell permeability, is a fundamental challenge when working with BRo5 molecules.
To move beyond this impasse, our group has investigated the application of prodrug groups to mask hydrogen bond donors and allow permeation of BRo5 molecules. Although prodrug strategies are widely used for masking cationic and anionic groups in both small and BRo5 molecules, our work suggest that this strategy can be extended to masking hydrogen bond donors. I will present our research, which interrogates model compounds and computational models, and suggests prodrugs for hydrogen bond donors may be promising tools for transforming Beyond Rule-of-Five molecules.