These results validate the docked pose of

These results validate the docked pose of the ALR2-3e complex in comparison to the docked complex of the ALR2-4c complex of which the compound docked completely out of the binding pocket of ALR2 (). This concludes to that the removal of the acetic myc pathway moiety leads to inactive or weakly active target compounds. Molecular dynamics study is a significant tool to understand the stability and the binding mode of the ligand-receptor interactions. It also helps to understand the dynamics of the protein, which represent the true nature of protein better than ordinary docking, which does not completely consider the dynamic of protein. The thermodynamic energy contribution of to the total binding free energy of the complex surmounts to the stability of in the ALR2 binding pocket and thus the stability of the complex during the simulation. summarizes the free binding energy of the system. In conclusion, we described in this work a novel series of quinazolinone-based rhodanine-3-acetic acid derivatives, developed as aldose reductase inhibitors. Tested in vitro against the target enzyme, they all proved to be active, showing IC values in the submicromolar/nanomolar range. Significantly, three out of the synthesized compounds, namely , , and , turned out to be almost 3-fold more active than the reference drug, epalrestat. The acetic acid moiety of the compounds proved to be a key functional element as its removal, as in compounds –, resulted in a remarkable decrease of inhibitory efficacy. Docking studies performed on the most active compound helped to understand the binding mode of the synthesized derivatives, thus providing the basis for further structure-guided design hypotheses of novel analogues with higher efficacy. In addition, exploring the selectivity of our novel ALR-2 inhibitors versus AKR1B10 and aldehyde reductase as well as pharmacokinetics of the most potent inhibitor is currently underway. Acknowledgements The authors are grateful to the Faculty of Pharmacy, Zagazig University, Egypt, for partial financial support of this work. C.L.M acknowledges Regione Toscana, Italy, for the financial support (IDARA Project, DD650/2014).
Introduction Diabetes is a chronic disease characterized by an impaired response to insulin and/or progressively reduced function of pancreatic β-cells [1]. All forms of diabetes are characterized by chronic hyperglycemia and the development of diabetes-specific microvascular pathology in the retina, renal glomerulus, and peripheral nerves, in addition to other tissues. Diabetes is also associated with accelerated atherosclerotic macrovascular disease, which affects arteries that supply the heart, brain, and lower extremities [2], [3]. Diabetes and its complications are a major cause of morbidity and mortality worldwide and currently affect almost 400 million people. The number of patients afflicted with type 2 diabetes is increasing rapidly in developed and developing countries [1], [4]. Aldose reductase is a central enzyme in the polyol pathway that belongs to the aldo-keto reductase superfamily and is implicated in aberrant glucose metabolism and diabetic complications [4], [5], [6]. Several studies have demonstrated the important role of aldose reductase in accelerating atherosclerosis and vascular injury associated with diabetes and aging. In hyperglycaemic conditions, aldose reductase catalyses NADPH-dependent reduction of glucose to sorbitol, which in turn is oxidized to fructose by an NAD+-dependent sorbitol dehydrogenase. Once sorbitol is accumulated inside the cells, it cannot diffuse easily across the cell membrane as a result osmotic pressure increases causing cellular damage. Aldose reductase inhibitors have been shown to reduce tissue sorbitol accumulation in diabetic animals and there are evidences that blockage of aldose reductase can have beneficial effect in diabetic complications [7], [8]. Up to now, various small molecule aldose reductase inhibitors have been evaluated in preclinical and clinical trials [9], [10], [11], [12]. However, epalrestat is the only commercially available aldose reductase inhibitor in Japan in 2015 [13]. Hence, there is an urgent need for new and effective aldose reductase inhibitors.