title: Identification of a novel selective serotonin reuptake inhibitor by coupling monoamine transporter-based virtual screening and rational molecular hybridization.
abstract: 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.
authors.affiliation: Division of Pharmaceutical Sciences, Mylan School of Pharmacy, Duquesne University, 600 Forbes Avenue, Pittsburgh, PA 15282, USA.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Nolan
authors.forename: David J
authors.initials: DJ
authors.lastname: Lapinsky
authors.forename: Jeffery N
authors.initials: JN
authors.lastname: Talbot
authors.forename: Martín
authors.initials: M
authors.lastname: Indarte
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Sankar
authors.initials: S
authors.lastname: Manepalli
authors.forename: Laura M
authors.initials: LM
authors.lastname: Geffert
authors.forename: Mary Ellen
authors.initials: ME
authors.lastname: Amos
authors.forename: Phillip N
authors.initials: PN
authors.lastname: Taylor
authors.forename: Jeffry D
authors.initials: JD
authors.lastname: Madura
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Surratt