Discovery of novel inhibitors of CDK2 using docking and physics-based binding free energy calculation

Lei Zheng, Yunpeng Yang, Jingxiao Bao, Liping He, Yifei Qi, John Z.H. Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Cyclin-dependent kinase (CDK) is a serine/threonine protein kinase family that cooperates with cyclin and plays an important role in the regulation of cell cycle. Cyclin-dependent kinase 2 is an important member of the CDK family and holds great promise as an anti-cancer drug target. In this study, we used molecular docking and physics-based binding free energy calculation method AS-IE that explicitly calculated protein-ligand binding entropy to discover novel inhibitors of CDK2. A total of 17 inhibitors were discovered with the best IC50 reaching ~2 μM. Decomposition of the binding free energy using AS-IE reveals key protein-ligand interactions that determines the activity. These results provided a good example of drug design using physics-based free energy calculation method such as AS-IE and the novel compounds offered a good start point for further development of CDK2 inhibitors.

Original languageEnglish (US)
Pages (from-to)662-673
Number of pages12
JournalChemical Biology and Drug Design
Volume99
Issue number5
DOIs
StatePublished - May 2022

Keywords

  • binding free energy calculation
  • CDK2
  • inhibitory activity
  • virtual screening

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Discovery of novel inhibitors of CDK2 using docking and physics-based binding free energy calculation'. Together they form a unique fingerprint.

Cite this