Excavation Of Key Anti-AD Component Hesperidin From Fructus Aurantii And Design Synthesis

Objective:In this study,based on the research method of network pharmacology to explore the key components of anti-AD in the traditional Chinese medicine Fructus Aurantii,and its related targets and pathways of acting on AD,and then use thekey component of anti-ADexcavated in Fructus Aurantii,hesperidin,as the lead compound to carry out the multi-target study of anti-AD derivatives.Fourteen hesperidin derivatives were designed and synthesized in expectation of getting anti-AD products with better activity.This study will provide new methods and ideas for the innovative research based on Citrus Aurantii,and also provide some newideas for the design of multi-targeted anti-ADdrugs.Methods:In this thesis,a series of active components with potential anti-AD activity in the traditional Chinese medicine FA,and their action targets and pathways were excavated based on web pharmacology.The quantitatively abundant component hesperidin from Fructus Aurantii was selected as the lead compound for anti-AD.A series of novel hesperidin derivatives were designed and synthesized based on the principles of pharmacophore splicing technology,and the binding ability and drug-like properties of hesperidin derivatives were predicted by molecular docking technology and ADMET database,and their in vitro cholinesterase inhibitory activities weremeasured by Ellen method.Results:1.The effective components of traditional Chinese medicine FA for the treatment of AD were extracted by network pharmacology,and the key components of FAfor anti-AD such as magnolol,naringenin,hesperidin and quercetin were screened by using degree-value,and their potential anti-AD targets were predicted by using OMIM and other databases,and from which IL1 B,AKT1,VEGFA,IL6,EGFR and JUN were screened.The key targets and key pathways such as MAPK signaling pathway,PI3K-Akt signaling pathway,TNF signaling pathway and EGFRtyrosine kinase inhibitor resistancewere selected.2.Based on the idea of "single-molecule-multi-target" drug design,we designed and synthesized a series of hesperidine-aminomethyl ester multi-target ligands with short synthetic routes and simple experimental operations.MS validation.The preliminary study of the interaction of hesperidin derivatives on AChE using molecular docking simulation technique revealed good interaction forces between them,and the ADMETlab database predicted that mostof the hesperidin derivatives have good drug-like properties,BBB,and OB.3.The AChE inhibitory activity of hesperidin derivatives was investigated by Ellman’s method to verify the results predicted by computer assistance,and the experiments showed that derivative i is a potent inhibitor of AChE with highinhibitory activity.Comparing the molecular docking model of derivative i with that of the lead compound hesperidin,it was found that although they both have the same hydrogen bond,the amino groups attached to them are different and the derivative has more interaction forces,such as the interaction with amino acid residue TYR341 via Pi-Donor Hydrogen Bond,the interaction with amino acid residue TRP286 via Pi-Pi T-shaped interconnection and Alkyl bond interconnection with LEU289,which may be responsible for exerting antioxidant properties and enhancing cholinesterase activity,theexact mechanism of which needs tobe investigated in thenext step.Conclusion:Based on the principle of pharmacophore splicing,a series of multi-targeted hesperidin derivatives with bio-synergistic effects were designed and synthesized by rational combination of splicing and introduction of amine groups,using hesperidin,the active ingredient of traditional Chinese medicine FA,as the lead compound.By improving the bioavailability of the lead compound,the log P value was adjusted to be used as a multi-targeted anti-AD ligand for the next step of research,in order to obtain more target anti-AD candidates,thus providing a theoretical basis for innovativedrug research of hesperidin.