Study On Pharmacophore Model Of Aldose Reductase Inhibitors

Diabetes mellitus, or simply diabetes, is a global burden of disease and is one of "the most serious three killers" of human beings. Diabetes has a high prevalence, annually increasing incidence with improvement of living level and ageing population. Diabetes can cause various complications so that the patient is under the risk of disability and even death. Currently, there is no any medicine can cure diabetes. Diabetes and its complications have significantly affected the wellbeing of human health, but the medication demand cannot be met. The aldose reductase inhibitor can limit polyol pathway by restricting the aldose reductase to prevent and delay complications of the diabetes. The only aldose reductase inhibitor in current market is epalrestat, but it is difficult to dissolve in water, so its bioavailability is low. Finding new aldose reductase inhibitors with high efficiency and low toxicity is therefore becomes the key of diabetes research. This article uses computer-aided drug design to build and validate 3D-pharmacophore models of aldose reductase inhibitor, uses obtained models to perform virtual screening, then confirms leading compounds through semi-flexible and flexible docking.Main research contents and results of this paper are as follows:Build 3D-pharmacophore models of aldose reductase inhibitor through receptor-based method, ligand-based method and receptor-ligand complex based method. Then build a test set to evaluate the models and choose the best one of each type for the next step.Conduct a 3D database searching using the 3 pharmacophore models in the Traditional Chinese Medicine database, and filter the results by Linpiski’s rules of five and Veber’s rule. The three models screened out 347、354、631 compounds respectively.Take semi-flexible docking firstly in consideration of that there are many compounds, and screen 258,302 and 537 compounds for three models respectively. Take consistency evaluation for the first 50 compounds ranked by scores in the screening results of the semi-flexible docking, and select 9 optimal compounds based on the evaluation results. In consideration of that it is potential for poses of the receptor and ligand to change, take full-flexible docking for above 9 compounds, and finally confirm that the rhinacanthin N and calcium rosmarinate can be used as lead compounds for design of the aldose reductase inhibitor, which providing theoretical basis for research and development of new medicines.