Peptide and Nonpeptide Macrocycles as Promising Chemotypes for Inhibiting Protein-Protein Interactions
There is a wealth of compelling protein-protein interaction, PPI, targets that cannot readily be inhibited using conventional druglike small molecules. Consequently, there is strong interest in noncanonical drug chemotypes as inhibitors of PPIs including, for example, peptide and nonpeptide macrocycles, peptide foldamers, and covalent inhibitors.
We are exploring the hypothesis that macrocyclic compounds, MCs, represent a privileged chemotype for inhibiting intracellular PPI targets. Large MCs can potentially exploit binding energy hot spots at a PPI surface site that are too widely spaced to be spanned by a smaller compound. Equally importantly, there is evidence that appropriately structured MCs can confer improved pharmaceutical properties – including, in particular, passive membrane permeability – compared to acyclic compounds of comparable molecular weight.
Here we describe approaches to identifying PPIs that constitute promising targets for macrocyclic inhibitors, as well as progress toward the development of design guidelines for macrocycles for use in drug discovery, based in part on a Machine Learning analysis of structural features and physicochemical properties relevant to passive membrane permeability.
AuthorsLauren A. Viarengo-Baker 1, Paula Ortet 1, Mengqi Zhong 1, Kristina Streu 1, Samantha N. Muellers 1, Lauren E. Brown 1, 3, Megan Egbert 2, John A. Porco, Jr. 1, 3, Sandor Vajda 1, 2, Karen N. Allen 1, 3, and Adrian Whitty 1, 3
AffiliationsDepartment of Chemistry 1, Department of Biomedical Engineering 2, and the Center for Molecular Discovery 3, Boston University, Boston, MA 02215, USA