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Creating and virtually screening databases of fluorescently-labelled compounds for the discovery of target-specific molecular probes

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Abstract

Our group has recently demonstrated that virtual screening is a useful technique for the identification of target-specific molecular probes. In this paper, we discuss some of our proof-of-concept results involving two biologically relevant target proteins, and report the development of a computational script to generate large databases of fluorescence-labelled compounds for computer-assisted molecular design. The virtual screening of a small library of 1,153 fluorescently-labelled compounds against two targets, and the experimental testing of selected hits reveal that this approach is efficient at identifying molecular probes, and that the screening of a labelled library is preferred over the screening of base compounds followed by conjugation of confirmed hits. The automated script for library generation explores the known reactivity of commercially available dyes, such as NHS-esters, to create large virtual databases of fluorescence-tagged small molecules that can be easily synthesized in a laboratory. A database of 14,862 compounds, each tagged with the ATTO680 fluorophore was generated with the automated script reported here. This library is available for downloading and it is suitable for virtual ligand screening aiming at the identification of target-specific fluorescent molecular probes.

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Acknowledgments

This research was supported with funds from the Thunder Bay Regional Research Institute, the Natural Sciences and Engineering Research Council of Canada (NSERC), and the RBC Royal Bank’s Dr. Mark Poznansky Mentorship Development Award. High-throughput computational work in this project was made possible with resources provided through SHARCNET (www.sharcnet.ca) and Lakehead University’s High Performance Computing Centre (LUHPCC). The authors wish to acknowledge Darryl Willick for his help with data transfer and manipulation.

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Authors and Affiliations

  1. Department of Chemistry, Lakehead University, Thunder Bay, ON, P7B 5E1, Canada

    Rhiannon L. Kamstra, Saedeh Dadgar, John Wigg & Wely B. Floriano

  2. Thunder Bay Regional Research Institute, Thunder Bay, ON, P7B 5E1, Canada

    Rhiannon L. Kamstra, Saedeh Dadgar, John Wigg, Morshed A. Chowdhury, Christopher P. Phenix & Wely B. Floriano

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  1. Rhiannon L. Kamstra
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  2. Saedeh Dadgar
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Correspondence to Wely B. Floriano.

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Kamstra, R.L., Dadgar, S., Wigg, J. et al. Creating and virtually screening databases of fluorescently-labelled compounds for the discovery of target-specific molecular probes. J Comput Aided Mol Des 28, 1129–1142 (2014). https://doi.org/10.1007/s10822-014-9789-0

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