Blind Docking of Manzamines into Glycogen Synthase Kinase-3?

Abstract

Manzamine alkaloids show diverse pharmacological activities and are potential leads for the treatment of neurodegenerative disorders since they inhibit glycogen synthase kinase-3β (GSK-3β), an attractive target for anti-Alzheimer therapy [1]. Though it is known that manzamines inhibit GSK-3β [2], the binding site into the kinase is not known. This hampers rational structure-based drug design of more potent manzamine analogs. To address this issue, we performed blind docking of manzamine A (MA) and its 8-hydroxy derivative (8MA) into GSK-3β. This included exploration of the possible binding pockets of Protein Data Bank structures 1q5 k, 1h8 f and 1i09 by scanning the whole protein surface and docking of MA and 8MA into any detected pockets. The figure shows GSK-3β (1q5 k): A. Four detected solvent pockets (white, green, cyan and yellow); B. Binding mode of MA into the ATP binding site (white in A); C. Polar interaction of MA with Arg141. Using FlexX for docking into the rigid apo enzyme (1i09), the energetics for binding into the ATP-competitive pocket and ATP-noncompetitive pockets were very similar.