Revisiting Pyrimidine-Embedded Molecular Frameworks to Probe the Unexplored Chemical Space for Protein–Protein Interactions

Protein–protein interactions (PPIs) are essential in numerous biological processes and diseases, making them attractive yet challenging drug targets. While many advances have been made in traditional drug discovery, targeting PPIs has been difficult due to a lack of specialized chemical libraries designed to modulate these interactions. Current libraries mainly focus on conventional target proteins like enzymes or receptors as substrate analogs rather than small-molecule modulators targeting PPIs. These traditional drug targets behave differently from PPIs. Conventional druggable targets have relatively small surfaces and binding pockets that have allowed them to be targeted with current libraries, but PPIs behave differently than these traditional drug targets. As a result, there is an urgent need for an innovative approach to expand the druggable space.