[P4-(OH)BPO] is a pillar[5]arene-derived molecular tube whose endo conformational isomer endo-[P4-(OH)BPO] possesses an inwardly pointing hydrogen-bond donor (OH) in its deep cavity, a strong hydrogen-bond acceptor (C=O) on its predominantly hydrophobic inner surface, which makes it ideal for mimicking a protein binding pocket. By measuring the binding affinity of this artificial protein binding pocket, we screened a library of various shape-complementary organic guests resembling the fragment ligands in fragment-based drug design (FBDD). On the basis of the binding affinity data for “fragment-pocket” complexes, two rationally designed “lead molecules” (HPA and HPF) were identified to be able to enhance binding affinity significantly by forming H-bonds with both the donor and acceptor of endo-[P4-(OH)BPO]. Our work demontrated potentials of developing pillar[n]arene-derived protein binding pocket-mimetic systems for studies on protein-ligand interactions and mechanisms of enzymatic reactions.

Model study on protein-ligand interaction and fragment-based drug design using an artificial protein binding pocket derived from pillar[5]arene

ACS Fall 2021

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