Identifying the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) as a potential target for hypericin--a theoretical...

Area of Science:

• Computational chemistry and molecular modeling
• Biochemistry and molecular biology
• Pharmacology and drug discovery

Background:

• The precise cellular target of the anti-cancer compound hypericin remains unknown.
• Understanding hypericin's target is crucial for advancing its therapeutic development.
• The sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) pump is a proposed target for hypericin.

Purpose of the Study:

• To investigate the potential interactions between hypericin and the SERCA pump using computational methods.
• To elucidate the binding sites and affinities of hypericin within SERCA.
• To provide insights for future drug development of hypericin as an anti-cancer agent.

Main Methods:

• Computational docking simulations to predict binding modes and affinities.
• Molecular dynamics simulations to analyze protein-ligand interactions over time.
• Comparison of hypericin's binding with known SERCA inhibitors like thapsigargin (TG) and di-tert-butylhydroquinone (BHQ).

Main Results:

• Hypericin exhibits strong binding in both transmembrane and cytosolic regions of SERCA isoforms.
• Calculated binding energies are comparable to or within the range of known SERCA inhibitors (TG, BHQ).
• Hydrophobic interactions suggest initial binding in the ER membrane, followed by diffusion into transmembrane pockets.

Conclusions:

• Hypericin likely binds to both SERCA isoforms, potentially acting as an inhibitor.
• Binding sites within the transmembrane region, accessible from the ER membrane, are highly probable.
• Under light irradiation, hypericin may generate singlet oxygen, leading to protein degradation or lipid peroxidation.