Abstract
Calbindin-D28K is a calcium sensor protein responsible for maintaining cellular calcium homeostasis and is known to have anti-apoptotic properties. The goals of this study were to propose calbindin-D28K peptide inhibitors based on known protein:protein interactions, in particular calbindin-D28K’s interaction with caspase-3. A total of 160,000 potential cyclic peptide inhibitors were computationally screened against calbindin-D28K. Several scoring mechanisms were used to validate each cyclic peptide inhibitor:calbindin-D28K interaction. A general consensus sequence of the cyclic peptides was shown to contain positive electrostatic characteristics with at least one aromatic-containing amino acid. Binding for one of the best scoring cyclic peptides is subsequently shown to alter the caspase-3 binding site on calbindin-D28K. Overall, these results suggest that calbindin-D28K is a druggable target via cyclic peptide inhibitors ultimately leading to the reactivation of caspase-3 and natural cell death.
Highlights
Chemotherapy and radiotherapy induce tumor cell death by activating apoptosis, a cellular pathway inactive in tumor cells
In our present study, we show that of the potential druggable sites within calbindin-D28K, the highest affinity location for the cyclic peptides corresponds to the area where linear peptides have previously been shown to bind [8]
The druggablity analysis performed in this study confirms the relevance of calbindin-D28K as a target for peptide therapeutics
Summary
Chemotherapy and radiotherapy induce tumor cell death by activating apoptosis (programmed cell death), a cellular pathway inactive in tumor cells. Any mechanism that inhibits apoptosis makes tumor cells resistant to these treatments. Strategies that sensitize tumor cells by targeting/enhancing the apoptotic pathway are of enormous interest. It is important to define a target that (i) has significant, well-established, anti-apoptotic function in the cell and (ii) is known to be expressed at higher levels in cancerous cells than normal cells. Considering all of these points, the anti-apoptotic calcium-binding protein calbindin-D28K is an especially appealing target
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