Journal
JOURNAL OF CHEMICAL INFORMATION AND MODELING
Volume 53, Issue 12, Pages 3202-3211Publisher
AMER CHEMICAL SOC
DOI: 10.1021/ci400481p
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Funding
- National Natural Science Foundation of China [81172919, 81130023, 30825042]
- State Key Laboratory of Drug Research
- National High Technology Research and Development Program of China (863 Program) [2012AA020301]
- State Key Program of Basic Research of China [2009CB918502, 2010CB912601, 2009CB522000, 2011CB5C4403]
- National Drug Innovative Program [2009ZX09301-011]
- Priority Academic Program Development of Jiangsu Higher Education Institutes (PAPD)
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The serotonin receptor subtype 1A (5-HT1AR) has been implicated in several neurological conditions, and potent 5-HT1AR agonists have therapeutic potential for the treatment of depression, anxiety, schizophrenia, and Parkinson's disease. In the present study, a homology model of 5-HT1AR was built based on the latest released high-resolution crystal structure of the beta(2)AR 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-HT1AR agonists. The obtained hits were subjected to 5-HT1AR 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-HT1AR The active 5-HT1AR model and dynamic. pharmacophore model obtained from this study can be used for future discovery and design of novel 5-HT1AR agonists. Also, by integrating all computational and available experimental data, a stepwise 5-HT1AR signal transduction model induced by agonist FW01 was proposed.
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