Plucking the high hanging fruit: a systematic approach for targeting protein-protein interactions.

Development of specific ligands for protein targets that help decode the complexities of protein-protein interaction networks is a key goal for the field of chemical biology. Despite the emergence of powerful in silico and experimental high-throughput screening strategies, the discovery of synthetic ligands that selectively modulate protein-protein interactions remains a challenge for bioorganic and medicinal chemists. This Perspective discusses emerging principles for the rational design of PPI inhibitors.

Assessing helical protein interfaces for inhibitor design.

Structure-based design of synthetic inhibitors of protein-protein interactions (PPIs) requires adept molecular design and synthesis strategies as well as knowledge of targetable complexes. To address the significant gap between the elegant design of helix mimetics and their sporadic use in biology, we analyzed the full set of helical protein interfaces in the Protein Data Bank to obtain a snapshot of how helices that are critical for complex formation interact with the partner proteins. The results of this study are expected to guide the systematic design of synthetic inhibitors of PPIs.

Guest-accelerated molecular rotor.

A molecular rotor was designed in which the rate of rotation is accelerated by guest complexation. The binding of an acetate guest to the urea groups lowers the barrier of the adjacent C(aryl)-N(imide) bond by 2 to 4 kcal/mol. This behavior is in contrast to most molecular rotors in which guest complexation slows rotation.

Mini review: protein-protein interactions in transcription: a fertile ground for helix mimetics.

Designed ligands that inhibit protein-protein interactions involved in gene expression are valuable as reagents for genomics research and as leads for drug discovery efforts. Selective modulation of protein-protein interactions has proven to be a daunting task for synthetic ligands; however, the last decade has seen significant advances in inhibitor design, especially for helical protein interfaces. This review discusses examples of transcriptional complexes targeted by designer helices.

A small molecule diacid with long-term chiral memory.

A small, axially chiral diacid was designed with chiral memory based on restricted rotation. Heating a racemic sample with a chiral alkaloid led to an enantiomeric excess of up to 40% ee. The guest-induced chirality was preserved on cooling to rt, which was maintained even in the absence of guest (t(1/2) = 14y).