# Multicomplex Pharmacophore Modeling of Estrogen Receptors Suggests the Probable Repurposing of Procaterol as an Antiproliferative Agent Against Breast Cancer Cells

## TL;DR

This study suggests repurposing the drug Procaterol as a potential treatment for breast cancer by targeting estrogen receptor beta.

## Contribution

A novel chemoinformatic strategy using multicomplex pharmacophore modeling to identify drugs with potential antiproliferative activity against breast cancer.

## Key findings

- Procaterol showed significant antiproliferative activity in breast cancer cell lines with IC50 values of 21.26 and 36.10 µM.
- Sobetirome, Labetalol, and Procaterol were identified as molecular hits with high affinity for the ERβ agonist pharmacophore.
- The in silico approach provides a strategy for drug repurposing and rational drug design for breast cancer.

## Abstract

Breast cancer (BC) is a malignant tumor that develops in the mammary gland due to uncontrolled cell proliferation. Estrogen receptor (ER) signaling, mediated by 17β-estradiol (E2), plays a crucial role in regulating cell proliferation, differentiation, and survival. Specifically, the binding of E2 to the estrogen receptor alpha (ERα) increases cell proliferation. Conversely, selective estrogen receptor beta (ERβ) agonists inhibit cancer cell proliferation by suppressing the expression of oncogenes, making ERβ an important therapeutic target. Given the urgent need for targeted and effective therapies for BC, we implemented a strategy based on multicomplex pharmacophores modeling of ERβ (MPMERβ) and ERα (MPMERα), performing a virtual cross-screening of databases of clinically approved and experimental drugs to identify those with high affinity and stereoelectronic complementarity with the ERβ agonist pharmacophore hypothesis. The implementation of a chemoinformatic strategy enabled the identification of Sobetirome, Labetalol, and Procaterol as molecular hits on the ERβ pharmacophore map. Procaterol showed the most significant antiproliferative activity in vitro assays, with IC50 values of 21.26 and 36.10 µM in MCF-7 and MDA-MB-231, respectively. It is imperative to note that these findings require experimental validation of the ERβ activation pathways to strengthen the possible therapeutic repurposing of the drugs selected through our in silico approach. Finally, this strategy not only facilitates drug repurposing under in silico simulation but also provides valuable information for the rational design of new drugs against BC.