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Structure paper

TitleFlexible scaffold-based cheminformatics approach for polypharmacological drug design.
Journal, issue, pagesCell, Vol. 187, Issue 9, Page 2194-2208.e22, Year 2024
Publish dateApr 25, 2024
AuthorsZhangcheng Chen / Jing Yu / Huan Wang / Peiyu Xu / Luyu Fan / Fengxiu Sun / Sijie Huang / Pei Zhang / He Huang / Shuo Gu / Bowen Zhang / Yue Zhou / Xiaobo Wan / Gang Pei / H Eric Xu / Jianjun Cheng / Sheng Wang /
PubMed AbstractEffective 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 ...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.
External linksCell / PubMed:38552625
MethodsEM (single particle) / X-ray diffraction
Resolution2.7 - 3.0 Å
Structure data

36634

8jt6

EMDB-36634, PDB-8jt6:
5-HT1A-Gi in complex with compound (R)-IHCH-7179
Method: EM (single particle) / Resolution: 3.0 Å

PDB-8jt8:
Crystal structure of 5-HT2AR in complex with (R)-IHCH-7179
Method: X-RAY DIFFRACTION / Resolution: 2.7 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-PLM:
PALMITIC ACID / Palmitic acid

ChemComp-J40:
[(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-phosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-3-tetradecanoyloxy-propan-2-yl] (5E,8E)-hexadeca-5,8,11,14-tetraenoate


ChemComp, No image

ChemComp-EZX:
Unknown entry

ChemComp-MG:
Unknown entry

ChemComp-OLC:
(2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate

ChemComp-1PE:
PENTAETHYLENE GLYCOL / precipitant*YM / Polyethylene glycol

ChemComp-PEG:
DI(HYDROXYETHYL)ETHER / Diethylene glycol

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
  • escherichia coli (E. coli)
KeywordsMEMBRANE PROTEIN / Serotonin receptor / 5-HT1AR / Gi-protein / GPCR / antipsychotic

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