Abstract
Cytochrome c (cyt c) release from mitochondria is accepted to be the point of no return for eliciting a cascade of interactions that lead to apoptosis. A strategy for containing sustained apoptosis is to reduce the mitochondrial permeability pore opening. Pore opening is enhanced by peroxidase activity of cyt c gained upon its complexation with cardiolipin in the presence of reactive oxygen species. Blocking access to the heme group has been proposed as an effective intervention method for reducing, if not eliminating, the peroxidase activity of cyt c. In the present study, using a combination of druggability simulations, pharmacophore modeling, virtual screening, and in vitro fluorescence measurements to probe peroxidase activity, we identified three repurposable drugs and seven compounds that are validated to effectively inhibit the peroxidase activity of cyt c.
Footnotes
- Received January 16, 2015.
- Accepted June 15, 2015.
This work was supported by the National Institutes of Health Institute of General Medical Sciences [Grant 5R01-GM099738-03 to I.B.] and Institute of Allergy and Infectious Diseases [Grant 5U1-9AI068021 to V.E.K., H.B., and I.B.]. A fellowship from Tsinghua University is acknowledged by F.H.
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- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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