Target specific virtual screening: Optimization of an estrogen receptor screening platform

In this work, we introduce a four-step scoring and filtering procedure, furnishing target specific virtual screening (TS-VS), which serves to minimize false positives resulting from conformational artifacts of the docking process and is optimized to converge on novel chemotypes of estrogen receptor alpha (ERα). As a proof of concept, VS of a commercial compound database was undertaken (SPECs database release: Aug 2005, 202 054 compounds in total), resulting in the identification of both previously known and novel putative ER scaffolds. Application of distance constraints within TS-VS allowed facile identification of three novel active ligands with ERα binding affinities (IC₅₀) of 1.4 μM, 57 nM, and 53 nM. Importantly, they all exhibited ERα over ERβ selectivity, with the most selective being 17-fold. The ligands also displayed low micomolar antiproliferative activity (7-15 μM) in the human MCF-7 breast cancer cell line.