Modelling of serotonergic receptors and molecular optimization of X-ray crystal structures of serotonin transporter and their interactions with exogenous compounds

摘要

The serotonin (5-hydroxytryptamine, 5-HT) receptors and transporter are in the serotonergicneurotransmission system, and believed to have a major role in pathology of depression. Theyare of pharmacological importance, being targeted by many nowadays antidepressants. It istherefore of great interest to understand their structural and functional properties fordevelopment of future drugs.There is generally little knowledge today about the effects of environmental toxicants on thehuman brain. If the exogenous compounds interact with the serotonin receptors andtransporter, they may interfere with the serotonergic neurotransmission in the brain andinterfere with the effects of the CNS drugs.Homology modelling is an in silico method used for prediction of the 3D structure ofstructurally unknown proteins. Models of serotonergic receptors (5-HT1A, 5-HT2A, 5-HT2C)were constructed by the homology approach with known structures in the PDB. The newlyreleased X-ray crystal structures of the human serotonin transporter (SERT) were alsoimported from the PDB and optimized with molecular modelling techniques. Moleculardocking was utilized to predict putative harmful effects and drug interactions of the toxicantsin the Tox21 database with these protein targets. Many toxic compounds were predicted tointeract with serotonergic receptors and the SERT and many of these had physiochemicalproperties that suggest that they may act in the CNS. Detailed interaction analysis of theselected compounds of serotonergic receptors and the SERT indicated that besides the crucialinteraction with an aspartic acid, aromatic interactions with phenylalanine residues are alsovery important. The obtained high CNS MPO scores and similar Glide scores between theknown high affinity binders and toxicants could suggest harmful effects and drug interactionsin serotonergic system of the CNS.