Theoretical investigations on maleimide and its indolyl derivatives: Rational drug design approach for PKCβII inhibitors

Protein kinase C βII (PKCβII) is preferentially activated during the hyperglycemic state and is associated with various diabetic complications. Hence its inhibition would be one of the ways to treat the diabetic complications. Maleimide constitutes the important moiety of PKCβII inhibitors, however till date no study on the significance of maleimide toward PKCβII inhibition is performed. Present report endeavors to study the electronic properties of maleimide with relevance to PKCβII inhibition. In the crystal structure of PKCβII, maleimide moiety of co-crystallized ligand 2-methyl-1H-indol-3-yl-BIM-1 is reported to form 3H-bonds, to reckon the importance of these H-bonds “H-bond interaction energy” was calculated using the ONIOM method, taking into consideration only the single point energy of the protein–ligand structure. New class of PKCβII inhibitors are designed based on above studies result and comparative analysis of rings similar to maleimide on the basis of various quantum chemical descriptors. The designed molecule showed good potency, binding interactions and scores in docking and ONIOM single point energy study.

► Keto form of maleimide become more prevalent with increasing molecular weight of PKCβII inhibitors.
► New inhibitors can be designed based on keto form of existing inhibitor.
► PKCβII inhibitors are designed by isoseric replacement of maleimide in 2mBIM.
► Newly designed molecule, des-14a is showing more potency than 2mBIM.
► It can be consider for further studies of PKCβII lead optimization.