jm1c01088_si_002.pdb (342.84 kB)
Rational Remodeling of Atypical Scaffolds for the Design of Photoswitchable Cannabinoid Receptor Tools
datasetposted on 2021-09-03, 13:36 authored by Tao Hu, Guoxun Zheng, Dongxiang Xue, Simeng Zhao, Fei Li, Fang Zhou, Fei Zhao, Linshan Xie, Cuiping Tian, Tian Hua, Suwen Zhao, Yueming Xu, Guisheng Zhong, Zhi-Jie Liu, Alexandros Makriyannis, Raymond C. Stevens, Houchao Tao
Azobenzene-embedded photoswitchable ligands are the widely used chemical tools in photopharmacological studies. Current approaches to azobenzene introduction rely mainly on the isosteric replacement of typical azologable groups. However, atypical scaffolds may offer more opportunities for photoswitch remodeling, which are chemically in an overwhelming majority. Herein, we investigate the rational remodeling of atypical scaffolds for azobenzene introduction, as exemplified in the development of photoswitchable ligands for the cannabinoid receptor 2 (CB2). Based on the analysis of residue-type clusters surrounding the binding pocket, we conclude that among the three representative atypical arms of the CB2 antagonist, AM10257, the adamantyl arm is the most appropriate for azobenzene remodeling. The optimizing spacer length and attachment position revealed AzoLig 9 with excellent thermal bistability, decent photopharmacological switchability between its two configurations, and high subtype selectivity. This structure-guided approach gave new impetus in the extension of new chemical spaces for tool customization for increasingly diversified photo-pharmacological studies and beyond.
typical azologable groupstype clusters surroundingoptimizing spacer lengthnew chemical spacesincreasingly diversified photohigh subtype selectivityexcellent thermal bistabilitycannabinoid receptor 2attachment position revealeddecent photopharmacological switchabilityembedded photoswitchable ligandsphotoswitchable ligandsphotopharmacological studiestwo configurationstool customizationrational remodelingphotoswitch remodelingpharmacological studiesoverwhelming majorityisosteric replacementcurrent approachescb2 antagonistcb2 ).binding pocketazobenzene remodelingazobenzene introductionatypical scaffoldsadamantyl arm