Targeting hORAI1-Mediated Calcium Influx in Triple-Negative Breast Cancer: A Computational Drug Discovery Approach.

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Store-operated calcium entry (SOCE) regulates cellular calcium homeostasis by restoring endoplasmic reticulum (ER) calcium levels.
• ORAI1, a key component of SOCE, is overexpressed in triple-negative breast cancer (TNBC) and drives cancer progression.
• The unknown atomic structure of human ORAI1 (hORAI1) hinders the development of targeted therapies.

Purpose of the Study:

• To model the closed state of hORAI1 as a potential therapeutic target.
• To identify small molecules that stabilize the closed state of hORAI1, inhibiting calcium influx in TNBC.
• To investigate the structural basis for targeting hORAI1 in cancer therapy.

Main Methods:

• Computational modeling of the closed state of hORAI1.
• Pharmacophore hypothesis screening of the COCONUT database using Mildronate analogues.
• Molecular docking, molecular dynamics simulations, and principal component/free energy landscape (PCA/FEL) analyses.

Main Results:

• Five compounds (CNP0006530, CNP0006516, CNP0008628, CNP0002844, CNP0004972) were identified that bind to hORAI1.
• These compounds demonstrated favorable docking scores and formed stable interactions with key residues (Glu106, Asp110), stabilizing the closed conformation.
• Molecular dynamics simulations confirmed the stability and compactness of the lead complexes in a membrane environment.

Conclusions:

• The closed state of hORAI1 is a viable target for therapeutic intervention in TNBC.
• Identified compounds show potential for inhibiting calcium influx and downstream oncogenic signaling.
• These findings offer new insights into hORAI1 gating mechanisms and suggest a novel strategy for cancer therapy.