Molecular Modeling of the 3D Structure of 5-HT1AR: Discovery of Novel 5-HT1AR 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.