Pillar[5]arene-Derived <i>endo</i>-Functionalized Molecular Tube for Mimicking Protein–Ligand Interactions
Zhuo Wang, Tao Chen, Hua Liu, Xiao‐Li Zhao, Wei‐Bo Hu, Hui Yang, Yahu A. Liu, Ke Wen
Abstract
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 molecular tube, [P4-(OH)BPO], whose endo conformational isomer endo-[P4-(OH)BPO] possesses an inwardly pointing hydrogen-bond (H-bond) donor (OH) in its deep cavity and a strong H-bond acceptor (C═O) on its predominantly hydrophobic inner surface, rendering it a perfect protein binding pocket mimetic. A fragment-based drug design model was established using endo-[P4-(OH)BPO] and a library of various shape-complementary fragment ligands (1–38). On the basis of the binding affinity data for “fragment-pocket” complexes G⊂endo-[P4-(OH)BPO] (G = 1–38), two rationally designed “lead molecules” (39 and 40) were identified as being able to enhance binding affinity significantly by forming H-bonds with both the donor and acceptor of endo-[P4-(OH)BPO]. The described work opens new avenues for developing pillar[n]arene-derived protein binding pocket-mimetic systems for studies of protein–ligand interactions and mechanisms of enzymatic reactions.