Open AccessIdentification of a Novel Selective Serotonin Reuptake Inhibitor by Coupling Monoamine Transporter-Based Virtual Screening and Rational Molecular Hybridization
Author(s) -
Tammy L. Nolan,
David J. Lapinsky,
Jeffery N. Talbot,
Martín Indarte,
Yi Liu,
Sankar Manepalli,
Laura M. Geffert,
Mary Amos,
Phillip N. Taylor,
Jeffry D. Madura,
Christopher K. Surratt
Publication year - 2011
Publication title -
acs chemical neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.158
H-Index - 69
ISSN - 1948-7193
DOI - 10.1021/cn200044x
Subject(s) - serotonin transporter , monoamine neurotransmitter , pharmacology , serotonin reuptake inhibitor , chemistry , fluvoxamine , serotonin , transporter , virtual screening , reuptake inhibitor , ligand (biochemistry) , norepinephrine transporter , antidepressant , serotonin plasma membrane transport proteins , pharmacophore , stereochemistry , biochemistry , biology , fluoxetine , receptor , endocrinology , gene , hippocampus
Ligand virtual screening (VS) using the vestibular binding pocket of a 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 K(i) = 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(1A) 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 [(3)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.