Molecular modeling, dynamics studies and density functional theory approaches to identify potential inhibitors of SIRT4 protein from Homo sapiens : a novel target for the treatment of type 2 diabetes

Abstract

Type 2 diabetes is one of the biggest health challenges in the world and WHO projects it to be the 7th leading cause of death in 2030. It is a chronic condition affecting the way our body metabolizes sugar. Insulin resistance is high risk factor marked by expression of Lipoprotein Lipases and Peroxisome Proliferator-Activated Receptor that predisposes to type 2 diabetes. AMP-dependent protein kinase in AMPK signaling pathway is a central sensor of energy status. Deregulation of AMPK signaling leads to inflammation, oxidative stress, and deactivation of autophagy which are implicated in pathogenesis of insulin resistance. SIRT4 protein deactivates AMPK as well as directly inhibits insulin secretion. SIRT4 overexpression leads to dyslipidimeia, decreased fatty acid oxidation, and lipogenesis which are the characteristic features of insulin resistance promoting type 2 diabetes. This makes SIRT4 a novel therapeutic target to control type 2 diabetes. Virtual screening and molecular docking studies were performed to obtain potential ligands. To further optimize the geometry of protein–ligand complexes Quantum Polarized Ligand Docking was performed. Binding Free Energy was calculated for the top three ligand molecules. In view of exploring the stereoelectronic features of the ligand, density functional theory approach was implemented at B3LYP/6-31G* level. 30 ns MD simulation studies of the protein–ligand complexes were done. The present research work proposes ZINC12421989 as potential inhibitor of SIRT4 with docking score (−7.54 kcal/mol), docking energy (−51.34 kcal/mol), binding free energy (−70.21 kcal/mol), and comparatively low energy gap (−0.1786 eV) for HOMO and LUMO indicating reactivity of the lead molecule.

Keywords:

• docking
• molecular dynamics
• quantum polarized ligand docking
• density functional theory
• binding free energy

Acknowledgements

JJ acknowledges DBT, ICMR [No. BIC/12(07)/2015] and DST [F.No. EMR/2016/000498] for providing financial assistance. The authors gratefully thank UGC-Innovative scheme [F.14-13/2013(Inno/ASSIST)] for providing Computational facility. JJ also acknowledges UGC Research Award [RA-2016-18-OB-TAM-7124].