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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors
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Development of Inhibitors of Protein-protein Interactions through REPLACE: Application to the Design and Development Non-ATP Competitive CDK Inhibitors

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Structural insights of cyclin dependent kinases: Implications in design of selective inhibitors

Sourav Kalra1, Gaurav Joshi2, Anjana Munshi1

  • 1Centre for Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, India.

European Journal of Medicinal Chemistry
|September 16, 2017
PubMed

Insights

This study compares Cyclin-dependent kinase (CDK) ATP binding sites to understand inhibitor specificity. Insights into structural differences aid in designing targeted CDK inhibitors for cancer therapy.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Medicinal Chemistry

Background:

  • Cyclin-dependent kinases (CDKs) are crucial regulators of the cell cycle, implicated in various cancers.
  • Existing CDK inhibitors often lack specificity, acting as pan inhibitors.
  • The development of specific inhibitors, like palbociclib for CDK4/6, highlights the need for targeted drug design.

Purpose of the Study:

  • To conduct a comparative analysis of structural differences in the ATP binding sites of various CDKs.
  • To correlate these structural variations with the specificity of known CDK inhibitors.
  • To provide insights for the rational design of novel, specific CDK inhibitors.

Main Methods:

  • Comparative structural analysis of CDK ATP binding sites.
  • Examination of ligand-receptor interactions for key CDKs.
  • Utilizing computer-aided drug design (CADD) principles.

Main Results:

  • Identification of key structural differences in CDK ATP binding pockets.
  • Depiction of specific ligand-receptor interactions dictating inhibitor binding.
  • Understanding the basis for differential inhibitor specificity across CDK family members.

Conclusions:

  • Structural insights into CDK ATP binding sites are critical for developing specific inhibitors.
  • Targeted inhibitor design can be advanced by understanding spatial features and interaction patterns.
  • This approach holds futuristic implications for precision oncology drug development.
Keywords:
CDK inhibitorsCancerCyclin dependent kinasesCyclinsDrug design

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