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Updated: Apr 7, 2026

Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Modelling the molecular mechanism of protein-protein interactions and their inhibition: CypD-p53 case study

S M Fayaz1, G K Rajanikant2

  • 1School of Biotechnology, National Institute of Technology Calicut, Calicut, 673601, India.

Molecular Diversity
|July 15, 2015
PubMed

Insights

Cyclophilin D (CypD) and p53 interaction is key in programmed cell death. Computational modeling revealed Cyclosporin A (CsA) inhibits this by binding to CypD, guiding the discovery of new inhibitors.

Area of Science:

  • Biochemistry and Molecular Biology
  • Computational Biology
  • Pharmacology

Background:

  • Cyclophilin D (CypD) regulates mitochondrial permeability and cell death.
  • The CypD-p53 interaction contributes to necroptosis, relevant in cardiovascular and neurological diseases.
  • Cyclosporin A (CsA) is a known inhibitor of the CypD-p53 interaction.

Purpose of the Study:

  • To model the CypD-p53 interaction and understand CsA's inhibitory mechanism.
  • To identify novel CypD inhibitors using structure-based computational methods.

Main Methods:

  • Molecular modeling of the CypD-p53 complex.
  • Structure-based drug design to identify potential inhibitors.
  • In silico validation of identified compounds.

Main Results:

  • p53 binds to the Cyclosporin A (CsA)-binding site on Cyclophilin D (CypD).
  • Computational modeling elucidated the molecular mechanism of CsA's interference.
  • Novel CypD inhibitors were identified through structure-based screening.

Conclusions:

  • The study provides insights into the CypD-p53 interaction and CsA inhibition.
  • The developed strategy can be applied to discover inhibitors of other protein-protein interactions (PPIs).
  • This approach aids in understanding and targeting PPIs involved in disease.
Keywords:
Cyclophilin DCyclosporin ANecroptosisNeurological disordersProtein–protein interactionsp53

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