Pillar[5]arene-Derived <i>endo</i>-Functionalized Molecular Tube for Mimicking Protein–Ligand Interactions

Artificial tubular molecular pockets bearing polar functionalities on their inner surface are useful model systems for understanding the mechanisms of protein–ligand interactions in living systems. We herein report a pillar[5]arene-derived tube, [P4-(OH)BPO], whose endo conformational isomer endo-[P4-(OH)BPO] possesses an inwardly pointing hydrogen-bond (H-bond) donor (OH) its deep cavity and strong H-bond acceptor (C═O) predominantly hydrophobic surface, rendering it perfect protein binding pocket mimetic. A fragment-based drug design was established using library various shape-complementary fragment ligands (1–38). On basis affinity data “fragment-pocket” complexes G⊂endo-[P4-(OH)BPO] (G = 1–38), two rationally designed “lead molecules” (39 40) were identified as being able to enhance significantly by forming H-bonds with both endo-[P4-(OH)BPO]. The described work opens new avenues developing pillar[n]arene-derived pocket-mimetic studies enzymatic reactions.