Computational Driven Study Of Cysteine-targeted Inhibitors

With series of characteristics like high affinity,long retention time,low dosage and low molecular weight,small molecule covalent drugs could effectively overcome the drug resistance caused by mutation in cancer or other diseases.According to the rational design and optimization of drugs by bioinformatics and computational biology method,the high efficiency characteristic of covalent drug can be effectively combination with the ability of specificity targeting,and reduction of the probability of Idiosyncratic Adverse Drug Reactions become possible in the meantime.As one of the mainly target sites of covalent inhibitors,there are various Cystiene targeted covalent drugs appeared on the market with widly attention and benefit.However,the discovery process of many covlanet drugs were full of contingency,for the lack of systematic research in drug target and drug dicsovery.By means of bioinformatics,virtual screening,molecular dynamics simulation and theoretical calculation and so on,this paper establishes the first targets database basing on Cys as the covalent targeting site,conducts the virtual screening of typical targeted protein(Xpol)of Cys and studies its combination mechanism with the inhibitor.Besides,it also researches and selects the drug-delivery receptor for the strcutural instability and poor oral bioavailability of the Xpol inhibitor in animal experiment with various molecular dynamics simulation methods.The main contents are as follow:1.By various bioinformatics methods we designed and developed Cysteinome database,the first online Cys targets database.The database bases on the information of literatures and databases concerned,counts and analyzes many information such as structures,related families and affiliated signaling pathways of the targeted protein.It also calculates and analyzes the physical and chemical properties of Cys site by the tools of computational biology and bioinformatics.Besides,Cysteinome records a lot of known Cys-targeted covalent modified molecules,include the structure and activity data.The researchers could understand the proteins containing modifiable Cys site systematically from the database.For the dicovery of target proteins and the design of covalent drugs with Cys site,this database does have a very high practical value.2.The swarm intelligence docking tool FIPSDock were used to screen the reactive small molecules recorded in Cysteinome toward the Xpol substrate binding pocket by combination of virtual screening technology and ADMET prediction.Serveal active natural products were obtained(sulforaphene,curcumin and caffeic acid phenethylester),and performed good Xpol-targeted inhibitory activity within assay.According to the combination of molecular dynamics simulation and free energy calculation,the binding mode between Xpol and inhibitors has also been studied,in particular the non-covalent interaction.The results demonstrate that covalent inhibitors need to interact with essential hydrophobic residues,polar residues steadily in the pocket except the appropriate reactivity of the electrophilic warhead,which is of vital significance to enhance the affinity and selectivity of covalent drugs to prolong the retention time and reduce the drug toxicity.3.Through the molecular dynamics simulation under multiple time scales,steered dynamics simulation,and the free energy calculation,the appropriate controlled-release receptor of the Xpol inhibitor was selected.And clarified the difference of the inhibitor molecule's motion state and the combination tendency between different receptors in micro perspective.Meanwhile,the long time scale molecular dynamics simulation was taken into the study of the drug-delivery systems to analyze the motion state and tendency of the inhibitor in different hostes under real time scale.The results confirm that the embedding capacity,contronlled-release ability of a-cyclodextrin are more suitable for the inhibitor molecule than ?-cyclodextrin.These methods for studying the properties of controlled-release receptors could help to understand the interal mechanism of the selectivity in different drug-delivery systems,and to provide theoretical support for rational choice of receptor.