Designing of potent anti-diabetic molecules by targeting SIK2 using computational approaches.

Abstract

Diabetes mellitus (DM) is one of the major health problems worldwide. WHO have estimated that 439 million people may have DM by the year 2030. Several classes of drugs such as sulfonylureas, meglitinides, thiazolidinediones etc. are available to manage this disease, however, there is no cure for this disease. Salt inducible kinase 2 (SIK2) is expressed several folds in adipose tissue than in normal tissues and thus SIK2 is one of the attractive targets for DM treatment. SIK2 inhibition improves glucose homeostasis. Several analogues have been reported and experimentally proven against SIK for DM treatment. But, identifying potential SIK2 inhibitors with improved efficacy and good pharmacokinetic profiles will be helpful for the effective treatment of DM. The objective of the present study is to identify selective SIK2 inhibitors with good pharmacokinetic profiles. Due to the unavailability of SIK2 structure, the modeled structure of SIK2 will be an important to understand the atomic level of SIK2 inhibitors in the binding site pocket. In this study, different molecular modeling studies such as Homology Modeling, Molecular Docking, Pharmacophore-based virtual screening, MD simulations, Density Functional Theory calculations and WaterMap analysis were performed to identify potential SIK2 inhibitors. Five molecules from different databases such as Binding_4067, TosLab_837067, NCI_349155, Life chemicals_ F2565-0113, Enamine_7623111186 molecules were identified as possible SIK2 inhibitors.