Niinivehmas, Sanna P.; Manivannan, Elangovan; Rauhamaki, Sanna; Huuskonen, Juhani; Pentikainen, Olli T.
Identification of estrogen receptor alpha ligands with virtual screening techniques

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 alpha (ER alpha). 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 pIC(50) value of 6.6, was identified. Furthermore, our small in-house compound collection of easy-to-synthesize molecules was virtually screened against ER alpha, yielding to five hit candidates, which were found to be active in vitro having pIC(50) values from 5.5 to 6.5. (C) 2015 Elsevier Inc. All rights reserved.


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