Discovery of natural estrogen receptor modulators with structure-based virtual screening

Area of Science:

• Natural Product Chemistry
• Molecular Pharmacology
• Medicinal Chemistry

Background:

• Estrogen receptors (ERα and ERβ) play critical roles in various physiological processes.
• Modulators of ER activity are of significant therapeutic interest for hormone-related diseases.
• Natural products represent a rich source of novel bioactive compounds.

Purpose of the Study:

• To identify novel estrogen receptor modulators from an in-house natural product database.
• To characterize the ER antagonistic activity and subtype selectivity of isolated cycloartane triterpenoids.

Main Methods:

• Structure-based virtual screening was employed to identify potential ER modulators.
• Yeast two-hybrid (Y2H) assays were used to confirm ER agonistic and antagonistic activities.
• Molecular docking simulations were performed to investigate binding modes and selectivity.

Main Results:

• Eleven compounds were identified as ER modulators, with 3 agonists and 8 antagonists.
• A novel series of cycloartane triterpenoids from Schisandra glaucescens Diels exhibited potent ER antagonistic effects.
• The most potent antagonist showed EC50 values of 2.55 μM for ERα and 4.68 μM for ERβ.

Conclusions:

• Novel cycloartane triterpenoids possess significant estrogen receptor antagonistic properties.
• These compounds demonstrate subtype selectivity for ERα and ERβ.
• The findings suggest potential for developing new therapeutics targeting estrogen receptor pathways.