基于细菌分裂蛋白ftsz靶点的药物设计及生物活性研究-药物化学专业论文.docx

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基于细菌分裂蛋白ftsz靶点的药物设计及生物活性研究-药物化学专业论文.docx

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基于细菌分裂蛋白ftsz靶点的药物设计及生物活性研究-药物化学专业论文

AbstractInthispaper,thecomplexstability,secondarystructure,proteinconformation,residuedistance,activesitevolume,andbindingfreeenergyoftheSaFtsZ(filamentoussensitivity divisionproteinZofStaphylococcusaureus)-GDP(Guanosinediphosphate)binarycomplex andthe3MBAderivativesternarycomplexwerestudiedbymoleculardynamicssimulations mechanics-Poisson-Boltzmannsurfacearea(MM-PBSA).Thenaseriesofcompoundswhich actedonFtsZwasdesignedbyLigBuilderv2.0.Andeighteencompoundswithpotentialdrug abilityandlowerdockingenergywereobtainedbyADME/T(absorption,distribution, metabolism,excretionandtoxicity)predictionandmoleculardocking.ConstructSaFtsZ-GDP-inhibitorternarycomplexbyselectingtypicalligands(02-49,09-32,146-75andthereported inhibitor9PC).The10nsmoleculardynamicssimulationswasperformed.Atlastbasedon SaFtsZproteinT7Loopactivepocket,wehaveestablishedavirtualscreeningworkflow usingmoleculardockingandADMETproperties.twenty-fivemoleculeswereboughtoutof aboutfiftycompoundsfromtheSpecsdatabaseandwereevaluatedfortheirantimicrobialactivities.Moleculardynamicssimulationsindicatethat:theSaFtsZ-GDPbinarycomplexintheabsenceofinhibitorwasunsteadyandtheresiduesofitsT7Loopareafluctuateobviously,atthesametime,thesecondarystructureofproteininT7Loopareachangesremarkably,theactivepocketvolumedecreasessharplyandthesubstratechannelsizealsobecomesnarrow andunstable.ButtheSaFtsZ-GDP-3MBAderivativesternarycomplexinthepresenceof theinhibitorPC190723orCompound1appearsinacompletelydifferentway.BothofthemcanformhydrogenbondingsandhydrophobiceffectswithhighaffinityonFtsZ,sothatsystemisstability.ButtheSaFtsZ-GDP-3MBAderivativesternarycomplexinthepresenceoftheinhibitorPC190723orCompound1appearsinacompletelydifferentway.Bothof themcanformhydrogenbondingsandhydrophobiceffectswithhighaffinityonFtsZ. However,fortheSaFtsZ-GDP-3MBAternarycomplex,theligandonlyformshydrophobiceffectswithpartialresiduesoftheactivepocketasafunctionofsimulationtime,withtheresultthat3MBAcouldnotstablyexistintheactivepocketforlowaffinity.Soantibac