Premium
Targeting PKC‐ β II and PKB Connection: Design of Dual Inhibitors
Author(s) -
Jain Kapil,
Ajay Dara,
Sobhia M. Elizabeth
Publication year - 2011
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201000082
Subject(s) - protein kinase c , pharmacophore , protein kinase b , virtual screening , signal transduction , chemistry , ligand (biochemistry) , small molecule , pharmacology , biology , microbiology and biotechnology , computational biology , cancer research , biochemistry , receptor
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.