Multitarget Design of Steroidal Inhibitors Against Hormone-Dependent Breast Cancer: An Integrated In Silico Approach

Juan Rodríguez-Macías; Oscar Saurith-Coronell; Carlos Vargas-Echeverria; Daniel Insuasty Delgado; Edgar A. Márquez Brazón; Ricardo Gutiérrez De Aguas; José R. Mora; José L. Paz; Marrero Ponce, Yovani

doi:10.3390/ijms26157477

Multitarget Design of Steroidal Inhibitors Against Hormone-Dependent Breast Cancer: An Integrated In Silico Approach

Journal

International Journal of Molecular Sciences

ISSN

1422-0067

Publisher

MDPI AG

Date Issued

2025-08-02

Author(s)

Juan Rodríguez-Macías

Oscar Saurith-Coronell

Carlos Vargas-Echeverria

Daniel Insuasty Delgado

Edgar A. Márquez Brazón

Ricardo Gutiérrez De Aguas

José R. Mora

José L. Paz

Type

text::journal::journal article

DOI

10.3390/ijms26157477

URL

https://scripta.up.edu.mx/handle/20.500.12552/12659

Abstract

Hormone-dependent breast cancer, particularly in its treatment-resistant forms, remains a significant therapeutic challenge. In this study, we applied a fully computational strategy to design steroid-based compounds capable of simultaneously targeting three key receptors involved in disease progression: progesterone receptor (PR), estrogen receptor alpha (ER-α), and HER2. Using a robust 3D-QSAR model (R2 = 0.86; Q2_LOO = 0.86) built from 52 steroidal structures, we identified molecular features associated with high anticancer potential, specifically increased polarizability and reduced electronegativity. From a virtual library of 271 DFT-optimized analogs, 31 compounds were selected based on predicted potency (pIC50 > 7.0) and screened via molecular docking against PR (PDB 2W8Y), HER2 (PDB 7JXH), and ER-α (PDB 6VJD). Seven candidates showed strong binding affinities (ΔG ≤ −9 kcal/mol for at least two targets), with Estero-255 emerging as the most promising. This compound demonstrated excellent conformational stability, a robust hydrogen-bonding network, and consistent multitarget engagement. Molecular dynamics simulations over 100 nanoseconds confirmed the structural integrity of the top ligands, with low RMSD values, compact radii of gyration, and stable binding energy profiles. Key interactions included hydrophobic contacts, π–π stacking, halogen–π interactions, and classical hydrogen bonds with conserved residues across all three targets. These findings highlight Estero-255, alongside Estero-261 and Estero-264, as strong multitarget candidates for further development. By potentially disrupting the PI3K/AKT/mTOR signaling pathway, these compounds offer a promising strategy for overcoming resistance in hormone-driven breast cancer. Experimental validation, including cytotoxicity assays and ADME/Tox profiling, is recommended to confirm their therapeutic potential.