Molecular Docking Study On The Mechanism Of Multi - Targets In The Treatment Of Hyperuricemia With Chicory

BackgroundThis research was part of the research of SRFDP (No.20130013120001) Which was also supported by Beijing University of Traditional Chinese Medicine (2013-JYB22-XS-086).Hyperuricemia is associated with and progression of gout, cardiovascular diseases, tumor lysis syndrome and renal disease, which also becomes an important risk factor of cardio-cerebral vascular diseases. Chinese medicine made a certain effect in the treatment of hyperuricemia for its efficacy and safety, however, the mechanism caused by the complexity of Chinese medicine and multiple target effect is not fully understood. The research employed Molecular docking in investigating chicory’s multi-targets mechanism, which has significant academic value and vital clinical significance.Based on the previous study, chicory has outstanding effect on lowering uric acid, which also has multiple target effect. The former research brilliantly expounds the mechanisms of chicory on controlling hyperuricemia from different angles. The research is focus on chicory’s Chemical substance in prevention and cure of hyperuricemia with Molecular docking technology, combined with biology research. And it make comprehensive analysis on the function mechanism of anti-hyperuricemia and explain chicory’s multi-target mechanisms, which is not only the basis for further Chinese medicines exploitation, but provides a new method for Chinese medicine multi-target mechanisms.Research Targets:1 Make it clear that chicory compounds are far more tha one directions, the diversity of their chemical space makes them Nature medicine.2. Virtual screening effect on the chemical composition of the target protein of hyperuricemia, clear Chicory in the treatment of hyperuricemia of multi target point.3 Multiple targets and diversity of common chicory clarify the molecular mechanism in the treatment of hyperuricemia.Research Content:This paper focuses on molecular docking and chicory’s anti-hyperuricemia effect, literature and computer simulation was carried out.(Ⅰ) Literature ReviewReview Ⅰ:Research progress in anti-hyperuricemia target proteins and medicineThe part presents a review of the literature on key proteins involved in the hyperuricemia process and status of Drug development, and investigates the feasibility of these proteins as anti-hyperuricemia target proteins from the views of regulatory gene, protein structure, physiological function and active site. The research progress of drugs is also displayed, which provide basis for the further study of chicory’s multi-target mechanisms on treatment of hyperuricemia.Review Ⅱ:The application progress of molecular docking in Chinese medicine researchThe part presents a review of the literature on application progress of molecular docking in Chinese medicine research, and discusses from four aspects:Chinese Medicine Pharmacological, the potency and efficacy of drugs, ADME/T and Lead compounds. With understanding of the current application scope, it provide basis for the study of pharmacodynamic mechanism of chicory for using molecular docking technology.(Ⅱ) Experiment ResearchTo Study the mechanisms of chicory’s multi-target on treatment of hyperuricemia, the first part reveals the material basis of chicory on lowering uric acid through analysis of chemical space diversity of chicory small molecular compound using molecular descriptors and principal component. The second part uses molecular docking technology combined with ADMET prediction and network analysis to clarify the complex mechanism of chicory small molecules acting on multiple targets and chicory’s multi-target mechanisms on treatment of hyperuricemia from the diversity of chemical composition and target function. In the Third part, the efficacy experiments of important chemical composition of Chicory on hyperuricemia animal model is invented to explain the rationality of the molecular docking experiment.Part Ⅰ The analysis of chicory small molecular compound chemical space diversityFormulated the material basis of chicory’s multi-targets effect on anti-hyperuricemia at chemical level. Elucidated chicory’s lowing serium urate acid.1. Consult literature and natural products database, collect and sort out the chemical composition of chicory, and download or use graphics rendering three-dimensional structure of the chemical composition of chicory.2. Employee E-dragon software to calculate the chicory small molecular compounds with molecular descriptor set, and analyze the drug-likeness of the small molecule compounds of chicory according to the result.3. Employee SPSS statistical software to make a principal component analysis of small molecule compounds of chicory and 11 hyperuricemia marketed drugs of 44 major molecular description, and project multidimensional described chemical space onto a two-dimensional plane, analyze directly the distribution of chicory small molecules and analyze the similarities and differences of chemical space of anti-hyperuricemia medicine.Part II Molecular docking between Chicory small molecule compounds and anti-hyperuricemia targetFormulated the mode of action of chicory’s multi-targets effect on anti-hyperuricemia at target level. Elucidated chicory’s lowing serium urate acid.1. Prepare anti-hyperuricemia target protein as the receptor library, chicory small molecular library as the ligand library, and use molecular docking software for docking. Analyze the docking results, analyzes by-with complex interaction patterns, analyzes the molecular mechanism of efficacy, and explain the result is reasonable.2. Use online tools admetSAR to analyze molecular docking for screening compounds by each protein for further absorption, distribution, metabolism, excretion and toxicity properties, screen for reasonable docking results further, and illustrate these compounds play a uric acid lowering efficacy possible mechanisms combined with ADME/T properties.Part Ⅲ Efficacy trials of Monomeric compounds-lactupicrinFormulated the important chemical compounds of chicory’s lowering uric acid effect at biological level. Elucidated chicory’s lowing serium urate acid.Select lactupicrin of chicory chemical composition to begin the pharmacodynamics experiments, which can inhibit multiple target proteins, can obtain by purchasing, and not yet carried out an important biological trails. The experiment takes quail of high-purine diet-induced hyperuricemia in animal models of classic group as the main study subject. With oral administration of lettuce bitter elements, observing the effect of uric acid, and detecting the activity of enzymes to assisted validate molecular docking results.Research results1. Small molecular libraries of chicory was established, contains 253 compounds, including 60 for metabolites of chicory compounds.2. Calculating 44 kinds of molecular descriptors between the 253 chicory compounds and 11 anti-hyperuricemia drugs, the results show most of small molecule comply with ’rule of five’, possess a good absorption and penetration ability. However, there are still a few compounds do not meet the rules, metabolism, distribution and excretion need to further analysis through ADME/T.3. From 44 molecular descriptor information of chicory extract two principal components and the cumulative contribution rate of 78%, from 44 molecular descriptor information of anti-hyperuricemia drugs extract two principal components and the cumulative contribution rate of 80%, both carry a large amount of chemical space information. Form the main scattered points, we can come to the conclusion that chicory chemical space distribution varied, and had a coincidence with anti-hyperuricemia drugs, this may be the characteristics of anti-hyperuricemia.4. Molecular docking results show that for the generate related enzymes including XOD、 5-NT、ADA、PNI、GuDa,70,98,56,4,83 points more than the original body of chicory small molecule compounds were screened. Analysis the characteristic of four compounds (XOD、5-NT、ADA、GuDa) and the activity of protein loci, take the top 10 compounds with active site function mode for instance, its show that has a good distribution and similar to positive control combining ways.5. Most of the chemical composition has a good nature of ADME/T, except for the individual compounds.6. Hyperuricemia model animal experiment. To observe the effect of the serum levels of the mountain lettuce on the uric acid in the hyperuricemia model. Lactucopicrin high (200 mg /kg in the first week (P=0.022), P=0.095 for the second week, the third week of 0.103), small dose group (100 mg/kg in the first week of P=0.033, P=0.059 for the second week, the third week, P= 0.058) can be significantly reduced serum uric acid level in quail model, and of xanthine oxidase and adenosine removal ammonia lyase has a certain degree of inhibition, of guanine deaminase no regulatory effect.Research conclusions1. The diversity of the spatial distribution of chicory chemical is the material basis in the treatment of hyperuricemia.2. Single component-multiple targets, multiple components-single target and single component-single target of synergistic effect is the mechanism of chicory small molecular compound in uric acid lowering, and single component-multiple targets is one of the most important.3. The molecular docking technology can be efficient and intuitive explanation the mechanism of chicory multiple target effect in the treatment of hyperuricemiaInnovation1. From two aspects:chemical space and targets to explain the mechanism of chicory in the treatment of hyperuricemia, to further clarified its true chemical substance.2. Using molecular docking intuitive and visual to explains the mechanism of multiple targets in the treatment of hyperuricemia.