Study Of AChE Inhibitors Discovery In Modified Buzhongyiqi Decoction Based On Data Mining

ObjectiveState Medical Masters professor Deng Tietao Application of modified Buzhongyiqi decoction treatment of myasthenia gravis (MG) in clinical for decades, the treatment effect is very significant. The study take modified Buzhongyiqi decoction for example, use the methods of data mining, identify target, building databases and virtual screening, to find the main herbs for target (AChE) in Jun, Chen, Zuo and Shi herbs; to discover main skeletal structure compoundof AChE inhibitors in major anti-AChE herbs; to discover new AChE inhibitors; be inspired from the traditional Chinese medicine compound, to quickly find a new method of active compounds.Methods1. In our work, acetylcholinesterase (AChE) was supposed as the target by studying the pathogenesis of MG, and obtained AChE protein structures from RCSB Protein Data Bank.2. And then we built herbs databases and AChE inhibitors database though data mining.3. The work applies the drug design techniques of Lipinski’s rule of five to get the drug-like compounds.4. By the virtual screen motheds of two dimensional similarity (2D), three dimensional similarity (3D) and glide docking to get the candidate AChE inhibitors from the herbs database.5. Sturcture analysis. We got a series of compounds with new scaffold by analysis.6. After searching in business database SPECS, we got 24 compounds of this new structure compounds and verified by Ellman assay. Finally,5 active compounds were found.7. Verified by molecular dynamics simulation methods to verify the virtual screening based on molecular docking to predict the reliability of the active compounds.ResultsThrough the study of the pathogenesis of MG, predict AChE as the main target of the disease. Flavonoids compounds is the main structure in modified Buzhongyiqi decoction that are resistance to AChE, at the same time, also found a class of compounds with new skeleton that show be able to anti-AChE. These five inhibitors are X4, X10, X11, X19 and X21, which IC50 are 6.5±0.23μM, 11.4 ± 2.72μM,7.1±1.34μM,10.9±0.48μM,2.3±0.15μM respectively, through experiment assay. The molecular dynamics simulations demonstrate that predicted binding free energy values were consistent with the bioactivity data of the new AChE inhibitors. This indicated that the binding modes were capable of virtually screening AChE inhibitors. This study demonstrates that structure-based drug discovery can be inspired by identifying active components from Chinese herbal medicines.ConclusionFirst, Jun and Shi herbs in modified Buzhongyiqi decoction play an important role of curing MG and, Chen and Zuo may play other roles.Second, the main active compounds are the flavonoid derivatives AChE inhibitors.Third, this study found five active AChE inhibitors compounds with the new structure.Finally, this paper provides a new research method, from the traditional classical prescription of traditional Chinese medicine, combined with the data mining method research of traditional Chinese medicine compound active ingredients, find active compounds.