Discovery of Serine/Threonine-Protein Kinase 4 Inhibitor by Molecular Docking and Molecular Dynamics Studies for Treatment of Diabetes

Nowadays, diabetes mellitus is a major challenge for human health. Serine/threonine-protein kinase 4 (STK4) is a main regulator of pancreatic β-cell death and dysfunction, and its over activation can lead to type 1 and type 2 diabetes. Deficiency of STK4 restores functional β-cells and normoglycemia. In the current study, for the first time, we used molecular modeling to discover a potent STK4 inhibitor.

In this study, among 51220 molecules in ZINC database, we used the molecular docking method for virtual screening process to select the potent and effective inhibitors against STK4. We used Desmond software for molecular dynamics (MD) simulations studies of the structures with the lowest free binding energy for 100 ns. The ADME properties of the selected compounds were calculated by Qikprop software.

Virtual screening results showed that compounds with ZINC ID of ZINC95918625, ZINC85569233, ZINC03874317, ZINC00105086 and ZINC14819359 can be considered as STK4 inhibitors. Among these compounds, ZINC95918625 had the lowest free binding energy (-11.67 kcal/mol). After the 100 ns MD studies, ZINC95918625 interacted with STK4 residues of Lys59, Glu73, Cys105, and Gly153 via hydrogen bonding. ADME analysis exhibited that all pharmaco-kinteic parameters of ZINC95918625 were within the reasonable range.

Our study can provide valuable information about new inhibitors for diabetes treatment. The findings of this study indicated that ZINC95918625 molecule could be used as a novel STK4 inhibitor in the future studies.