PMID- 22892582
OWN - NLM
STAT- MEDLINE
DCOM- 20130109
LR  - 20211203
IS  - 1463-9084 (Electronic)
IS  - 1463-9076 (Linking)
VI  - 14
IP  - 36
DP  - 2012 Sep 28
TI  - Identifying the sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) as a potential 
      target for hypericin--a theoretical study.
PG  - 12637-46
LID - 10.1039/c2cp42237a [doi]
AB  - 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.
FAU - Eriksson, Emma S E
AU  - Eriksson ES
AD  - Department of Chemistry and Molecular Biology, University of Gothenburg, 412 96 
      Goteborg, Sweden. emma.eriksson@chem.gu.se
FAU - Eriksson, Leif A
AU  - Eriksson LA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120815
PL  - England
TA  - Phys Chem Chem Phys
JT  - Physical chemistry chemical physics : PCCP
JID - 100888160
RN  - 0 (Anthracenes)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hydroquinones)
RN  - 26XK13B61B (2,5-di-tert-butylhydroquinone)
RN  - 5QD5427UN7 (Perylene)
RN  - 67526-95-8 (Thapsigargin)
RN  - 7V2F1075HD (hypericin)
RN  - EC 3.6.3.8 (Sarcoplasmic Reticulum Calcium-Transporting ATPases)
SB  - IM
MH  - Anthracenes
MH  - Antineoplastic Agents/*chemistry/pharmacology
MH  - Enzyme Inhibitors/chemistry/pharmacology
MH  - Humans
MH  - Hydroquinones/chemistry/pharmacology
MH  - Models, Molecular
MH  - *Molecular Dynamics Simulation
MH  - Molecular Structure
MH  - Perylene/*analogs & derivatives/chemistry/pharmacology
MH  - Sarcoplasmic Reticulum/*enzymology/metabolism
MH  - Sarcoplasmic Reticulum Calcium-Transporting ATPases/antagonists & 
      inhibitors/*chemistry/metabolism
MH  - Structure-Activity Relationship
MH  - Thapsigargin/chemistry/pharmacology
EDAT- 2012/08/16 06:00
MHDA- 2013/01/10 06:00
CRDT- 2012/08/16 06:00
PHST- 2012/08/16 06:00 [entrez]
PHST- 2012/08/16 06:00 [pubmed]
PHST- 2013/01/10 06:00 [medline]
AID - 10.1039/c2cp42237a [doi]
PST - ppublish
SO  - Phys Chem Chem Phys. 2012 Sep 28;14(36):12637-46. doi: 10.1039/c2cp42237a. Epub 
      2012 Aug 15.