Molecular modeling studies of [4-(3 H-benzoimidazol-5-yl)-pyrimidin-2-yl]-amine-based CDK4 inhibitors

Future Med Chem. 2021 Aug;13(16):1317-1339. doi: 10.4155/fmc-2020-0393. Epub 2021 Jul 2.

Abstract

Aim: CDK4 is a promising target for breast cancer therapy. This study aimed to explore the structure-activity relationship of CDK4 inhibitor abemaciclib analogs and design potent CDK4 inhibitors for breast cancer treatment. Methods & results: A faithful 3D quantitative structure-activity relationship model was established by molecular docking, comparative molecular field analysis and comparative molecular similarity index analysis based on 56 abemaciclib analogs. Molecular dynamics simulation studies revealed the key residues of the interaction between CDK4 and inhibitors. Four novel inhibitors with satisfactory predicted binding affinity to CDK4 were designed. Conclusion: The 3D quantitative structure-activity relationship and molecular dynamics simulation studies provide valuable insight into the development of novel CDK4 inhibitors.

Keywords: 3D-QSAR; CDK4; CoMFA; CoMSIA; MD simulation; abemaciclib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclin-Dependent Kinase 4 / antagonists & inhibitors*
  • Cyclin-Dependent Kinase 4 / metabolism
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Quantitative Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • CDK4 protein, human
  • Cyclin-Dependent Kinase 4