Computational Design of Cyclic Peptide Inhibitors of the Anti-Apoptotic Protein Calbindin-D28K

Benjamin G Bobay, Logan R B

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.