The exact cellular target for the potent anti-
cancer agent
hypericin has not yet been determined; this thus encourages the application of computational chemistry tools to be employed in order to provide insights that can be employed in further
drug development studies. In the present study computational docking and molecular dynamics simulations are applied to investigate possible interactions between
hypericin and the Ca(2+) pump SERCA as proposed in the literature.
Hypericin was found to bind strongly both in pockets within the transmembrane region and in the cytosolic region of the
protein, although the two studied
isoforms of SERCA differ slightly in their preferred binding sites. The calculated binding energies for
hypericin in the four investigated sites were of the same magnitude as for
thapsigargin (TG), the most potent SERCA inhibitor, or in the range between TG and
di-tert-butylhydroquinone (BHQ), which is also known to possess inhibitory activity. The hydrophobic character of
hypericin indicates that the molecule initially binds in the ER membrane from which it diffuses into the transmembrane region of the
protein and to binding pockets therein. The transmembrane TG and BHQ binding pockets provide suitable locations for
hypericin as they allow for favourable interactions with the
lipid tails that surround these. High binding energies were noted for
hypericin in these pockets and are expected to constitute highly possible binding sites due to their accessibility from the ER membrane.
Hypericin most likely binds to both
isoforms of SERCA and acts as an inhibitor or, under light irradiation, as a
singlet oxygen generator that in turn degrades the
protein or induces lipid peroxidation.