8JT8

Crystal structure of 5-HT2AR in complex with (R)-IHCH-7179

8JT8 の概要

• エントリーDOI: 10.2210/pdb8jt8/pdb
• 分子名称: 5-hydroxytryptamine receptor 2A,Soluble cytochrome b562, MAGNESIUM ION, 1-(4-fluorophenyl)-4-[(7R)-2,5,11-triazatetracyclo[7.6.1.0^2,7.0^12,16]hexadeca-1(15),9,12(16),13-tetraen-5-yl]butan-1-one, ... (7 entities in total)
• 機能のキーワード: gpcr, serotonin receptor, antipsychotic, membrane protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46079.44

構造登録者

Chen, Z.,Fan, L.,Wang, S. (登録日: 2023-06-21, 公開日: 2024-02-28, 最終更新日: 2024-11-13)

主引用文献

Chen, Z.,Yu, J.,Wang, H.,Xu, P.,Fan, L.,Sun, F.,Huang, S.,Zhang, P.,Huang, H.,Gu, S.,Zhang, B.,Zhou, Y.,Wan, X.,Pei, G.,Xu, H.E.,Cheng, J.,Wang, S.
Flexible scaffold-based cheminformatics approach for polypharmacological drug design.
Cell, 187:2194-2208.e22, 2024

PubMed Abstract: Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HTR to act as an antagonist and a "stretching-up" binding pose at 5-HTR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HTR for psychoactive symptoms and activating 5-HTR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.

PubMed: 38552625
DOI: 10.1016/j.cell.2024.02.034

実験手法

X-RAY DIFFRACTION (2.7 Å)