Analysis of Binding Mode of Vibsanin A with Protein Kinase C C1 Domains: an Experimental and Molecular Dynamics Simulation Study

Vibsanin A (VibA), isolated from Viburnum odoratissimum, binds to and activates protein kinase C (PKC) isozymes to induce leukemia cell differentiation. VibA is a promising seed compound for developing PKC-activating drugs because it exhibits anti-proinflammatory activity, atypical to PKC activators. However, the role of hydrogen bond-forming functional groups and the precise binding mode with C1 domains in PKC isozymes remains unknown. In this study, we evaluated the PKC-binding ability of natural vibsanins and synthetic 1'-desoxo-VibA ( 1 ) and performed molecular dynamics simulation of membrane/C1 domain-bound VibA to predict the binding mode of VibA with C1 domains. Experimental and simulation results indicated that the ester group in VibA is involved in CH-O hydrogen bonds with PKC C1 domains. Alter-natively, a growth-inhibition assay against leukemia cells revealed that the ester group of VibA negatively affects antiproliferative activity.