Structure‐Activity Relationship Studies of Hydantoin‐Cored Ligands for Smoothened Receptor

An underside binding site was recently identified in the transmembrane domain of smoothened receptor (SMO). Herein, we report efforts in the exploration of new insights into the interactions between the ligand and SMO. The hydantoin core in the middle of the parent compound was found to be highly co...

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Published in:ChemistryOpen (Weinheim) 2021-10, Vol.10 (10), p.1028-1032
Main Authors: Liu, Yang, Zhou, Fang, Ding, Kang, Xue, Dongxiang, Zhu, Zhihao, Li, Cuixia, Li, Fei, Xu, Yueming, Xu, Fei, Le, Zhiping, Zhao, Suwen, Tao, Houchao
Format: Article
Language:English
Subjects:
Acidification
anti-cancer
Benzene
Binding Sites
Chirality
Communication
Communications
Crystallization
Design
Drug resistance
halogen bonding
Hydantoin
Hydantoins - pharmacology
Hydrocarbons
Hydrogen
Ligands
molecular dynamics
Receptors
Smoothened Receptor
structural biology
Structure-Activity Relationship
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container_end_page 1032
container_issue 10
container_start_page 1028
container_title ChemistryOpen (Weinheim)
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creator Liu, Yang
Zhou, Fang
Ding, Kang
Xue, Dongxiang
Zhu, Zhihao
Li, Cuixia
Li, Fei
Xu, Yueming
Xu, Fei
Le, Zhiping
Zhao, Suwen
Tao, Houchao
description An underside binding site was recently identified in the transmembrane domain of smoothened receptor (SMO). Herein, we report efforts in the exploration of new insights into the interactions between the ligand and SMO. The hydantoin core in the middle of the parent compound was found to be highly conservative in chirality, ring size, and substituents. On each benzene at two ends, a plethora of variations, particularly halogen substitutions, were introduced and investigated. Analysis of the structure‐activity relationship revealed miscellaneous halogen effects. The ligands with double halogen substituents exhibit remarkably enhanced potency, providing promising candidates that potentially overcome the common drug resistance and useful heavy‐atom labeled chemical tools for co‐crystallization studies of SMO. A series of diaryl hydantoin analogs were synthesized and evaluated in the inhibition of Hedgehog pathway by targeting the smoothened receptor. Double halogen substituents introduced at two ends of the molecule greatly enhanced the potency.
doi_str_mv 10.1002/open.202100216
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subjects Acidification
anti-cancer
Benzene
Binding Sites
Chirality
Communication
Communications
Crystallization
Design
Drug resistance
halogen bonding
Hydantoin
Hydantoins - pharmacology
Hydrocarbons
Hydrogen
Ligands
molecular dynamics
Receptors
Smoothened Receptor
structural biology
Structure-Activity Relationship
title Structure‐Activity Relationship Studies of Hydantoin‐Cored Ligands for Smoothened Receptor
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