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Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular

Nagasundaram N1, Hailong Zhu1, Jiming Liu1

  • 1Department of Computer Sciences, Hong Kong Baptist University, Kowloon Tong, Hong Kong.

Plos One
|August 8, 2015
PubMed

Insights

This study identifies harmful genetic variations in the CDK4 gene, crucial for cell cycle progression and cancer development. Computational methods revealed specific mutations affecting protein interactions, paving the way for targeted cancer therapies.

Area of Science:

  • Genetics
  • Molecular Biology
  • Computational Biology

Background:

  • The cyclin-dependent kinase 4 (CDK4)-cyclin D1 complex regulates cell cycle G1 to S phase transition.
  • Somatic genetic variations in CDK4 are frequently observed in various cancers, implicating its abnormal function in tumorigenesis.
  • CDK4 is a genetically validated therapeutic target due to its critical role in cancer development.

Purpose of the Study:

  • To identify deleterious single nucleotide polymorphisms (nsSNPs) in the CDK4 gene using an integrated computational approach.
  • To predict the impact of these nsSNPs on protein-protein (CDK4-cyclin D1) and protein-ligand (CDK4-flavopiridol) interactions.
  • To discover potential inhibitors for mutant CDK4 proteins, aiding in the development of targeted cancer therapies.

Main Methods:

  • Systematic computational analysis to identify deleterious nsSNPs in the CDK4 gene.
  • Prediction of nsSNP effects on CDK4-cyclin D1 and CDK4-flavopiridol interactions using molecular docking and dynamic simulations.
  • Virtual screening to identify potential drug candidates that bind to mutated CDK4 conformations.

Main Results:

  • Five highly deleterious nsSNPs were identified: R24C, Y180H, A205T, R210P, and R246C.
  • These nsSNPs were shown to significantly affect CDK4-cyclin D1 and CDK4-flavopiridol interactions.
  • Specific compounds, including 5_7_DIHYDROXY_ 2_ (3_4_5_TRI HYDROXYPHENYL) _4H_CHROMEN_ 4_ONE, diosmin, and rutin, demonstrated significant binding affinities to mutated CDK4 variants.

Conclusions:

  • Genetic variations in CDK4 are linked to cancer development through altered protein interactions.
  • The identified nsSNPs provide insights into the molecular mechanisms of CDK4 in cancer.
  • This study facilitates the discovery of novel, molecularly targeted therapies for personalized cancer treatment by identifying potential drug candidates for specific CDK4 mutations.

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