title: Targeting PKC-β II and PKB Connection: Design of Dual Inhibitors.
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.
authors.affiliation: Centre 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.
authors.forename: Kapil
authors.initials: K
authors.lastname: Jain
authors.affiliation: Centre 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.
authors.forename: Dara
authors.initials: D
authors.lastname: Ajay
authors.affiliation: Centre 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. mesophia@niper.ac.in.
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Sobhia
keywords: Docking; Dual inhibitor; Pharmacophore mapping; Protein kinase B (PKB); Protein kinase C (PKC); Virtual screening