Modelling the molecular mechanism of protein–protein interactions and their inhibition: CypD–p53 case study

Cyclophilin D (CypD) is an important regulatory protein involved in mitochondrial membrane permeability transition and cell death. Further, the mitochondrial CypD–p53 axis is an important contributor to necroptosis, a form of programmed necrosis, involved in various cardiovascular and neurological disorders. The CypD ligand, Cyclosporin A (CsA), was identified as an inhibitor of this interaction. In this study, using computational methods, we have attempted to model the CypD–p53 interaction in order to delineate their mode of binding and also to disclose the molecular mechanism, by means of which CsA interferes with this interaction. It was observed that p53 binds at the CsA-binding site of CypD. The knowledge obtained from this modelling was employed to identify novel CypD inhibitors through structure-based methods. Further, the identified compounds were tested by a similar strategy, adopted during the modelling process. This strategy could be applied to study the mechanism of protein–protein interaction (PPI) inhibition and to identify novel PPI inhibitors.