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.
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 β₂AR 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.
Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University , Shanghai 201203, China.
Lili
L
Xu
Shanglin
S
Zhou
Kunqian
K
Yu
Bo
B
Gao
Hualiang
H
Jiang
Xuechu
X
Zhen
Wei
W
Fu
D020134:Catalytic Domain; D030562:Databases, Protein; D055808:Drug Discovery; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010879:Piperazines / Q000737:chemistry*; D011485:Protein Binding; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry*; D018343:Receptors, Adrenergic, beta-2 / Q000737:chemistry; D058825:Serotonin 5-HT1 Receptor Agonists / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry*; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
D007211:Indoles; D008024:Ligands; D010879:Piperazines; D018343:Receptors, Adrenergic, beta-2; D058825:Serotonin 5-HT1 Receptor Agonists; D054852:Small Molecule Libraries; D044282:Receptor, Serotonin, 5-HT1A; D016244:Guanosine 5'-O-(3-Thiotriphosphate)