Docking Studies of Curcumin and Analogues with Various Phosphodiesterase 4 Subtypes.

INTRODUCTION: The primary aim of this study is to understand the binding of curcumin and its analogues to different PDE4 subtypes and identification of the role of PDE4 subtype inhibition in the anti-inflammatory property of curcumin. Docking analysis has been used to acquire the above mentioned structural information and this has been further used for designing of curcumin derivatives with better anti-inflammatory activity.

MATERIALS AND METHOD: Curcumin and its analogues were subjected to docking using PDE4A, PDE4B, PDE4C and PDE4D as the target. A data set comprising of 18 analogues of curcumin was used as ligands for docking of PDE4 subtypes. Curcumin was used as the standard for comparison. Docking was performed using AutoDock Vina 1.1.2 software integrated in LigandScout 4.1. During this process water molecules were removed from proteins, charges were added and receptor structures were minimized by applying suitable force fields. The docking scores were compared, and the selectivity of compounds for PDE4B over PDE4D were calculated as well. Key Finding: All curcumin analogues used in the study showed good binding affinity with all PDE4 subtypes, with evident selectivity towards PDE4B subtype. The binding of analogue A11 provides the highest binding energy among all ligands.

CONCLUSIONS: Curcumin and analogues have moderate to strong affinity towards all PDE4 subtypes and have evident selectivity towards PDE4B. Oxygen atom of methoxy groups plays a key role in protein binding and any alterations could interfere with the protein binding. Tetrahydropyran side chain and heterocyclic rings are also suggested to be helpful in protein binding.