Journal of Molecular Graphics and Modelling 2016-03-01

Identification of estrogen receptor α ligands with virtual screening techniques.

Sanna P Niinivehmas, Elangovan Manivannan, Sanna Rauhamäki, Juhani Huuskonen, Olli T Pentikäinen

Index: J. Mol. Graph. Model. 64 , 30-Sep, (2016)

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Abstract

Utilization of computer-aided molecular discovery methods in virtual screening (VS) is a cost-effective approach to identify novel bioactive small molecules. Unfortunately, no universal VS strategy can guarantee high hit rates for all biological targets, but each target requires distinct, fine-tuned solutions. Here, we have studied in retrospective manner the effectiveness and usefulness of common pharmacophore hypothesis, molecular docking and negative image-based screening as potential VS tools for a widely applied drug discovery target, estrogen receptor α (ERα). The comparison of the methods helps to demonstrate the differences in their ability to identify active molecules. For example, structure-based methods identified an already known active ligand from the widely-used bechmarking decoy molecule set. Although prospective VS against one commercially available database with around 100,000 drug-like molecules did not retrieve many testworthy hits, one novel hit molecule with pIC50 value of 6.6, was identified. Furthermore, our small in-house compound collection of easy-to-synthesize molecules was virtually screened against ERα, yielding to five hit candidates, which were found to be active in vitro having pIC50 values from 5.5 to 6.5. Copyright © 2015 Elsevier Inc. All rights reserved.