Pillar[5]arene-Derived endo-Functionalized Molecular Tube for Mimicking Protein-Ligand Interactions
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作者
CONFORMATIONAL SELECTION; INDUCED FIT; GUEST; BINDING; HOST; COMPLEXATION; DESIGN; SPACE; ENCAPSULATION; RECOGNITION
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刊物名称
J. Org. Chem.
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年、卷、文献号
2021, 86,
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关键词
CONFORMATIONAL SELECTION; INDUCED FIT; GUEST; BINDING; HOST; COMPLEXATION; DESIGN; SPACE; ENCAPSULATION; RECOGNITION
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摘要
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[S]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 A basis of the binding affinity data for fragment-pocket complexes G subset of 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.
