Targeting the Side-Chain Convergence of Hydrophobic α-Helical Hot Spots To Design Small-Molecule Mimetics: Key Binding Features for i, i + 3, and i + 7.

The conformational convergence of hydrophobic α-helical hot spots was revealed by analyzing α-helix-mediated protein-protein interaction (PPI) complex structures. The pharmacophore models were derived for hydrophobic α-helical hot spots at positions i, i + 3, and i + 7. These provide the foundation for designing generalizable scaffolds that can directly mimic the binding mode of the side chains of α-helical hot spots, offering a new class of small-molecule α-helix mimetics. For the first time, the protocol was developed to identify the PPI targets that have similar binding pockets, allowing evaluation of inhibitor selectivities between α-helix-mediated PPIs. The mimicry efficiency of the previously designed scaffold 1 was disclosed. The close positioning of this small molecule to the additional α-helical hot spots suggests that the decoration of this series of generalizable scaffolds can conveniently reach the binding pockets of additional α-helical hot spots to produce potent small-molecule inhibitors for α-helix-mediated PPIs.