Targeting PKC-β II and PKB Connection: Design of Dual Inhibitors
Kapil Jain1, Dara Ajay1, M Elizabeth Sobhia2
1Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S Nagar - 160062, Punjab, India phone: +91-172-221468286-2025; fax: +91-172-2214692.
Abstract:
Protein kinase C (PKC) has been the center of many cell signaling pathways. PKC isoforms, specifically PKC-β II is linked to both diabetic complications as well as in promotion of angiogenesis and regulation of cancers. PKC-β II activates the PKB/Akt pathway. Enzastaurin, a selective PKC-β II inhibitor has been found to inhibit PKB/Akt by suppressing the regulation of various cancerous pathways. In the present work, we carried out an in depth study on the binding mode of inhibitors of PKC-β II, enzastaurin and ruboxistaurin with the active site residues of PKB and PKC-β II. A ligand based approach has been further used to determine the pharmacophoric features and spatial arrangement of molecules, having common properties necessary for appropriate binding to the active site of both targets. Virtual screening of the respective pharmacophores of both proteins led to identification of hits which may be useful for treatment of diabetic complications and cancer. The study has highlighted important features that may be considered in the future for designing novel inhibitors.
Insights
This study investigates how Protein Kinase C beta II (PKC-β II) inhibitors like enzastaurin bind to PKB and PKC-β II. Findings aid in designing new treatments for diabetic complications and cancer.
Area of Science:
- Molecular biology
- Pharmacology
- Computational chemistry
Background:
- Protein Kinase C (PKC) signaling pathways are crucial in cellular functions.
- PKC-β II is implicated in diabetic complications, angiogenesis, and cancer progression.
- PKC-β II activates the PKB/Akt pathway, a target in cancer therapy.
Purpose of the Study:
- To elucidate the binding modes of PKC-β II inhibitors (enzastaurin, ruboxistaurin) with PKB and PKC-β II active sites.
- To identify pharmacophoric features for effective binding to both targets.
- To discover novel therapeutic agents for diabetic complications and cancer.
Main Methods:
- In-depth analysis of inhibitor binding modes.
- Ligand-based approach for pharmacophore identification.
- Virtual screening of identified pharmacophores.
Main Results:
- Detailed understanding of enzastaurin and ruboxistaurin binding interactions.
- Identification of key pharmacophoric features for PKC-β II and PKB inhibition.
- Discovery of potential drug candidates through virtual screening.
Conclusions:
- The study provides insights into the molecular basis of PKC-β II inhibition.
- Identified pharmacophores can guide the design of novel inhibitors.
- Potential for developing new treatments for cancer and diabetic complications.
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