Molecular Docking And QSAR Analysis Of Dioxins And Its Inhibitors

With the development of standard of living and the improvement of civilization, it gives prominence to the problem of environment pollution increasingly. A sort of persistent organic pollutants, which is represented by Dioxins, has caused severe harm to the environment for mankind's survival and to be the focus of widespread concern of international community. Especially after the foods dioxin pollution affair caused by animal feed in Belgium in May, 1999, it became the studying hotspot for environmental researchers all over the world.Dioxins include PCDDs and PCDFs. They have showed high immunotoxicity, teratogenesis, carcinogenesis and to be environment pollutant with higher toxicity. Study of Molecular Biology shows that dioxins express their toxicity by interaction with a kind of receptor protein, which is AhR. The toxicity of dioxins is dependent on their affinity to AhR. And if this affinity data would be gotten, we could know their harm degree and have ability to analyze and control these toxins quickly and effectively.Flavonoids are natural compounds with low molecular weight widespread in the plants as well as an important effective element in Chinese traditional medicine, which can be extracted from vegetables, fruits, beans and teas. It is shown by the experimentation that, at dietary levels flavonoids can inhibit the toxicity effect of dioxins. However, we are not much clear about their inhibitory mechanism.In this paper, we have studied the interaction between dioxins and AhR roundly, with the link of the newest research findings referring to the toxicity of dioxins all over the world and based on the study of Molecular Biology, while utilizing the methods of homo-modeling and molecular docking. In the choice of 75 PCDDs and 135 PCDFs as research objects and mouse AhR PAS-B gotten by homo-modeling as receptor, we built the reliable theoretical model. At the same time, we have built quantitative structure-activity relationship (QSAR) model which taking into account the information of ligand and receptor. We picked up the parameters from docking result such as minimum docking energy, H-bond distance between active amino acids and ligand, using for QSAR study for part of PCDFs which have bio-activity data, gotten the QSAR model for toxicity and variables. It is shown that there is good interrelationship between toxicity and variables for the interaction of dioxins and AhR, with R~2 value of 0.893 and q~2 value of 0.825, which established the academic base for forecasting toxicity effects of unknown dioxins. Meanwhile, on the basic of related literatures, combined with docking and QSAR methods, we have also studied the inhibitory mechanism of flavonoids. It's shown from the result that flavonoids likely inhibit the transformation of AhR by the way of competition binding to AhR. And there is also some quantitative structure-activity relationship between IC50 and docking parameters.