Identification of a novel selective serotonin reuptake inhibitor by coupling monoamine transporter-based virtual screening and rational molecular hybridization

Tammy L. Nolan, David J. Lapinsky, Jeffery N. Talbot, Martín Indarte, Yi Liu, Sankar Manepalli, Laura M. Geffert, Mary Ellen Amos, Phillip N. Taylor, Jeffry D. Madura, Christopher K. Surratt

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    15 Citations (Scopus)

    Abstract

    © 2011 American Chemical Society. 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 K<inf>i</inf>= 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<inf>1A</inf>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.
    Original languageEnglish
    Pages (from-to)544-552
    JournalACS Chemical Neuroscience
    Volume2
    Issue number9
    DOIs
    Publication statusPublished - 8 Jun 2011

    Keywords

    • Depression
    • Molecular docking
    • Molecular hybridization
    • Monoamine
    • Neurotransmitter transporter
    • Virtual screening

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  • Cite this

    Nolan, T. L., Lapinsky, D. J., Talbot, J. N., Indarte, M., Liu, Y., Manepalli, S., Geffert, L. M., Amos, M. E., Taylor, P. N., Madura, J. D., & Surratt, C. K. (2011). Identification of a novel selective serotonin reuptake inhibitor by coupling monoamine transporter-based virtual screening and rational molecular hybridization. ACS Chemical Neuroscience, 2(9), 544-552. https://doi.org/10.1021/cn200044x