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

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.     

Assessment of the chitosan-functionalized graphene oxide as a carrier for loading thioguanine,an antitumor drug and effect of urea on adsorption process: Combination of DFT computational and molecular dynamics simulation studies

In this study, the interaction thioguanine (TG) anticancer drug with the functionalized graphene oxide (GO) nanosheet surface is theoretically studied in both gas phase and separately in physiological media using the density functional theory (DFT) calculations. DFT calculations indicated the adsorption and solvation energies are negative for f-GONS/TG complexes which propose the adsorption process of TG molecule onto the f-GONS surface is possible from the energetic viewpoint. QTAIM calculations confirm the nature of partially covalent-partially electrostatic between drug and nanosheet. These results are sorely relevant that an approach for loading of TG molecule is the chemical modification of GO using covalent functionalization which can serve as a nanocarrier to load drug molecules. Moreover, to understand the effect of urea on the nature of the interaction between TG and f-GONS, molecular dynamics (MD) simulation was employed. The results indicated that in the presence of urea the adsorption process gets affected and leads to instability of system, while the affinity of the TG for adsorption onto GO surface is increased in pure water.

Communicated by Ramaswamy H. Sarma     

The chemistry of the CuB site in cytochrome c oxidase and the importance of its unique His-Tyr bond

The Cu_B metal center is at the core of the active site of the heme-copper oxidases, comprising a copper atom ligating three histidine residues one of which is covalently bonded to a tyrosine residue. Using quantum chemical methodology, we have studied the Cu_B site in several redox and ligand states proposed to be intermediates of the catalytic cycle. The importance of the His-Tyr crosslink was investigated by comparing energetics, charge, and spin distributions between systems with and without the crosslink. The His-Tyr bond was shown to decrease the proton affinity and increase the electron affinity of both Tyr-244 and the copper. A previously unnoticed internal electronic equilibrium between the copper atom and the tyrosine was observed, which seems to be coupled to the unique structure of the system. In certain states the copper and Tyr-244 compete for the unpaired electron, the localization of which is determined by the oxygenous ligand of the copper. This electronic equilibrium was found to be sensitive to the presence of a positive charge 10 Å away from the center, simulating the effect of Lys-319 in the K-pathway of proton transfer. The combined results provide an explanation for why the heme-copper oxidases need two pathways of proton uptake, and why the K-pathway is active only in the second half of the reaction cycle.