Computational Chemical and Structural Biology
Structural Determinants of Antidepressant Drugs – A Detailed Analysis of Antidepressants Interactions with Serotonin and Norepinephrine Transporters
The biogenic monoamine neurotransmitters, serotonin transporter (SERT), norepinephrine transporter (NET), and to a lesser extent the dopamine transporter (DAT), are targets for antidepressant drugs. Selective serotonin reuptake inhibitors (SSRI), serotonin norepinephrine reuptake inhibitors (SNRI), and norepinephrine reuptake inhibitors (NRI), contain structurally similar scaffolds that target SERT with high potency (SSRI), SERT and NET with similar potency (SNRI), or exclusively NET (NRI). Extensive structure activity relationship (SAR) studies have identified important ligand fragments that selectively inhibit NET or SERT; however, little is known about the antidepressant complex with SERT/NET. Crystal structures of SERT/NET have not been resolved but a crystal structure homolog from /Aquifex aeolicus/ LeuT provides a template for comparative modeling of SERT/NET. The ligand/protein interface software suite, RosettaLigand, will be used to dock antidepressants into an already made comparative model. RosettaLigand stochastically docks ligand rotamers while simultaneously optimizing sidechain interactions for docked poses.