8JT8

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

Summary for 8JT8

• Entry DOI: 10.2210/pdb8jt8/pdb
• Descriptor: 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)
• Functional Keywords: gpcr, serotonin receptor, antipsychotic, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 46079.44

Authors

Chen, Z.,Fan, L.,Wang, S. (deposition date: 2023-06-21, release date: 2024-02-28, Last modification date: 2024-11-13)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.7 Å)