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

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Pharmacology

Background:

• Estrogen receptor alpha (ERalpha) is a key target in breast cancer therapy.
• Virtual screening (VS) methods often yield false positives due to conformational artifacts.
• Novel ERalpha modulators with improved selectivity and efficacy are needed.

Purpose of the Study:

• To develop and validate a target-specific virtual screening (TS-VS) procedure.
• To identify novel chemotypes targeting ERalpha with high selectivity.
• To assess the antiproliferative activity of identified ligands in breast cancer cells.

Main Methods:

• A four-step scoring and filtering procedure (TS-VS) was implemented.
• A commercial compound database (202,054 compounds) was screened.
• Distance constraints were applied within TS-VS to refine ligand identification.

Main Results:

• TS-VS successfully minimized false positives and identified novel ERalpha scaffolds.
• Three novel ERalpha ligands were discovered with IC50 values of 1.4 µM, 57 nM, and 53 nM.
• These ligands demonstrated ERalpha over ERbeta selectivity (up to 17-fold) and antiproliferative activity (7–15 µM) in MCF-7 cells.

Conclusions:

• The TS-VS method is effective for identifying selective ERalpha ligands.
• Novel ERalpha modulators with therapeutic potential were discovered.
• This approach can accelerate the discovery of new cancer therapeutics.