Identification of a Novel Selective Serotonin Reuptake Inhibitor by Coupling Monoamine Transporter-Based Virtual Screening and Rational Molecular Hybridization

Ligand virtual screening (VS) using the vestibular binding pocket of a three-dimensional (3-D) monoamine transporter (MAT) computational model followed by in vitro pharmacology led to the identification of a human serotonin transporter (hSERT) inhibitor with modest affinity (hSERT <i>K</i><sub>i</sub> = 284 nM). Structural comparison of this VS-elucidated compound, denoted MI-17, to known SERT ligands led to the rational design and synthesis of DJLDU-3-79, a molecular hybrid of MI-17 and dual SERT/5-HT<sub>1A</sub> receptor antagonist SSA-426. Relative to MI-17, DJLDU-3-79 displayed 7-fold improvement in hSERT binding affinity and a 3-fold increase in [<sup>3</sup>H]-serotonin uptake inhibition potency at hSERT-HEK cells. This hybrid compound displayed a hSERT:hDAT selectivity ratio of 50:1 and a hSERT:hNET (human norepinephrine transporter) ratio of >200:1. In mice, DJLDU-3-79 decreased immobility in the tail suspension test comparable to the SSRI fluvoxamine, suggesting that DJLDU-3-79 may possess antidepressant properties. This proof of concept study highlights MAT virtual screening as a powerful tool for identifying novel inhibitor chemotypes and chemical fragments for rational inhibitor design.