J Chem Inf Model - Molecular modeling of the 3D structure of 5-HT(1A)R: discovery of novel 5-HT(1A)R agonists via dynamic pharmacophore-based virtual screening.

Tópicos

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Resumo

The serotonin receptor subtype 1A (5-HT(1A)R) has been implicated in several neurological conditions, and potent 5-HT(1A)R agonists have therapeutic potential for the treatment of depression, anxiety, schizophrenia, and Parkinson's disease. In the present study, a homology model of 5-HT(1A)R was built based on the latest released high-resolution crystal structure of the ?2AR in its active state (PDB: 3SN6). A dynamic pharmacophore model, which takes the receptor flexibility into account, was constructed, validated, and applied to our dynamic pharmacophore-based virtual screening approach with the aim to identify potential 5-5-HT(1A)R agonists. The obtained hits were subjected to 55-HT(1A)R binding and functional assays, and 10 compounds with medium or high K(i) and EC50 values were identified. Among them, FW01 (K(i) = 51.9 nM, EC50 = 7 nM) was evaluated as the strongest agonist for 5-HT(1A)R. The active 5-HT(1A)R model and dynamic pharmacophore model obtained from this study can be used for future discovery and design of novel 5-HT(1A)R agonists. Also, by integrating all computational and available experimental data, a stepwise 5-HT(1A)R signal transduction model induced by agonist FW01 was proposed.

Resumo Limpo

serotonin receptor subtyp htar implic sever neurolog condit potent htar agonist therapeut potenti treatment depress anxieti schizophrenia parkinson diseas present studi homolog model htar built base latest releas highresolut crystal structur ar activ state pdb sn dynam pharmacophor model take receptor flexibl account construct valid appli dynam pharmacophorebas virtual screen approach aim identifi potenti htar agonist obtain hit subject htar bind function assay compound medium high ki ec valu identifi among fw ki nm ec nm evalu strongest agonist htar activ htar model dynam pharmacophor model obtain studi can use futur discoveri design novel htar agonist also integr comput avail experiment data stepwis htar signal transduct model induc agonist fw propos

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