Design And Synthesis Of Antiviral Active Compounds Based On Tobacco Mosaic Virus Helicase | Posted on:2018-10-20 | Degree:Master | Type:Thesis | Country:China | Candidate:Z X Li | Full Text:PDF | GTID:2351330536488578 | Subject:Applied Chemistry | Abstract/Summary: | PDF Full Text Request | Tobacco mosaic virus(TMV)is a kind of important plant virus which belongs to species of tobamovirus.It can infect tobacco and other plant species of Solanacae family.The mechanisms of chemical control measures currently used include suppressing the infection of host by TMV,inhibiting the multiplication and spread of TMV cell,and inducing the resistance in the host.On the other hand,drug discoveries targeting animal virus also pay attention to functional proteins that are essential for virus replication,such as reverse transcriptase,polymerase,protease and helicase.In this thesis,molecular design based on the structure of TMV RNA helicase was carried out and the target molecules were synthesized and bioassayed to find high efficient chemical entity with novel mechanism against TMV.Helicase is a kind of hydrogen bonding of the enzyme and hydrolysis ATP to provide energy for replication,there are all kinds of helicase have ATP-helicase function in organism.Based on the structure of the ATP ligand,we design,synthesis and anti-TMV bioactivities of 25 nucleoside phosphonate analogues.The antiviral activity test was carried out by the Half-leaf method with commercial product Ningnanmycin as control,the result of bioassay showed that compound 7 displayed good antiviral activity against TMV at 500 ?g/m L,compound 7 curative effect(52.8?6.1%)and protection effect(72.2?3.8%)can compare with Ningnanmycin curative effect(54.2±2.9%)and protection effect(70.2±2.2%).Triazole compound than other alkaloids against tobacco Mosaic virus activity more obvious.So we design,synthesis and anti-TMV bioactivities of 24 triazole phosphonate analogues.The antiviral activity test was carried out by the Half-leaf method with commercial product Ningnanmycin as control,the result of bioassay showed that compound 37(54.4±3.7%)、39(56.2±5.8%)、40(54.7±5.2%)、45(52.6±3.8%)displayed considerable antiviral activity against TMV compared with Ningnanmycin curative effect(54.2±2.9%)at 500 ?g/m L.It can be find that the ortho-compound bioassay activity remarkabler than meta-compound and para-compound,the bioactivity can be improved deeply if linked with heterocycle or aromatic ring contain Electron-withdrawing groups;therefore,we still derive 12 triazole phosphonate analogues.The antiviral activity test was carried out by the Half-leaf method with commercial product Ningnanmycin as control,the result of bioassay showed that compound 53(48.4±3.5%)、58(47.3±1.4%)displayed considerable antiviral activity against TMV compared with Ningnanmycin curative effect(50.2±1.9%)at 500 ?g/m L.Preliminary structure activity relationship analysis indicated that the ortho-intermediate with contain electronic absorption of benzene acetylene of the target compound have a considerable activity compared to Ningnanmycin,With in 3 or 4 contains alkynyl heterocycle of the target compound,also have the obvious bioactivity to TMV.compound 7 was selected to dock with TMV helicase by SYBYL,SWISS-MODEL server was applied for homology modeling of TMV helicase with the previously reported crystal structure of ToMV RNA helicase being used as template.The quality of the model structure was analyzed and verified by the Ramachandran plot.The result showed that all the residues are in the allowed region.Amber 12 was applied for the molecular dynamic optimization of the model structure.The skeleton structure was considered as the active conformation of the helicase-ATP complex.Using this helicase-ATP complex structure as the receptor and the ATP binding site as the active pocket,docking with compound 7.The PYMOL showed that the distances of O atom of carbonyl group in 7 to N atom in His375 is 2.89 A?,the distances of O atom of carbonyl group in 7 to H atom in Gln378 is 3.51 A?,the distances of O atom of carbonyl group in 7 to O atom in Pro273 is 2.77 A?. | Keywords/Search Tags: | Tobacco mosaic virus, helicase, Alkaloid, triazole, homology modeling, bioactivity, docking | PDF Full Text Request | Related items |
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