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THE BIOLOGICAL TARGET DERIVED PHARMACOPHORIC MODEL FOR 5-HT7 SEROTONIN RECEPTOR ANTAGONISM

Marcin Kołaczkowski 1Mateusz Nowak 2Maciej Pawłowski 1Andrzej J. Bojarski 2

1. Jagiellonian University, Collegium Medicum, Department of Pharmaceutical Chemistry, Medyczna 9, Kraków 30-688, Poland
2. Polish Academy of Sciences, Institute of Pharmacology, Department of Medicinal Chemistry, Smętna 12, Kraków 31-343, Poland

Abstract
The biological target derived pharmacophoric model is presented for 5-HT7 serotonin receptor antagonism. It was generated based on results of automated docking of examples of all known antagonists classes to the conformational ensemble of rhodopsin based receptor models. The methodology reflects conformational flexibility of both ligand and receptor. Current pharmacophoric model is divided into two sub-models: (1) "affinity" model - including features common for all (nonselective and selective) antagonists; (2) "selectivity" model - explaining which pharmacophoric features are responsible for selectivity toward 5-HT7 receptor. Nonselective antagonists, described by the model (1), are situated along TM3, occupying the cavity formed by TMHs 4-6 and interacting specifically with Asp3.32, Phe6.61, Phe6.62, Ser5.42 and optionally Phe3.28, Tyr7.43. Selective antagonists form the network of interactions with the residues from TMHs 3 and 7: Asp3.32, Phe3.28, Tyr7.43 and Arg7.36 and optionally Phe6.61, Phe6.62. It is postulated that if the latter interaction pattern dominates over the former one, selectivity toward 5-HT7 receptor is enhanced.

Acknowledgement

This study was partially supported by the research Grant no. 012/2002 from the Polish Pharmacy and Medicine Development Foundation, given by the POLPHARMA Pharmaceutical Works.

 

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Submitted: 2006-01-31 14:21
Revised:   2009-06-07 00:44