制藥工程 專業(yè)英語 Unit 25ppt課件

TheprofessionalEnglishofpharmaceuticalengineering,WangXinliangEastChinaUniversityofScienceandTechnology,Words,physicochemicalpharmacologicalantidoteantimetaboliteantiulcerleuk(a)emias(leucemias)arthritispoliomyelitisinvivo/invitromalignantcondescensionserendipityparadigmfreeenergy/enthalpy/entropyretrospectiverepositorycircumspectregressionanalysisCADD:Computer-AidedDrugDesignSAR:structure-activityrelationshipmorbidity(mortality),a.物理化學(xué)的，物化的a.藥理學(xué)的n.解毒劑n.抗代謝物（藥）n.抗胃潰瘍的n.白血病n.關(guān)節(jié)炎n.脊髓灰質(zhì)炎；小兒麻痹癥在體內(nèi)/體外a.惡性的；有害的；n.懷惡意的人n.謙虛；屈尊；傲慢態(tài)度n.意外發(fā)現(xiàn)；偶然發(fā)現(xiàn)n.范例n.自由能/焓/熵a.回顧性的；懷舊的；n.回顧展n.儲藏室；知識庫；智囊團(tuán)a.周到的；慎重的回歸分析計算機(jī)輔助藥物設(shè)計構(gòu)效關(guān)系n.發(fā)病率；致病率(死亡率；死亡數(shù)),目前的藥物設(shè)計與其說是富有成績（成效），不如說是充滿希望的。這意味著在最廣泛意義上運用過去所認(rèn)知的生物活性與物化特性之間的關(guān)系，并且希望可以預(yù)測還未合成出來的化合物在藥理學(xué)的成功。,Drugdesigntodayismoreofahopethananachievement.Itmeanstheapplicationofpreviouslyrecognizedcorrelationsofbiologicalactivitywithphysicochemicalcharacteristicsinthebroadestsense,inthehopethatthepharmacologicalsuccessofanotyetsynthesizedcompoundcanbepredicted.,但目前所使用的藥物很少是完全按照這種方法被發(fā)現(xiàn)出來。膽堿酯酶抑制劑解毒劑吡啶肟甲基碘化物，抗胃潰瘍藥西咪替丁，以及對抗白血病有活性的一些抗代謝藥都是這樣的例子。,Fewdrugsinusetodaywerediscoveredentirelyinthisway.Thecholinesteraseinhibitorantidotepyridinealdoximemethiodide,theantiulcerdrugCimetidine,andsomeantimetabolitesactiveagainstleukemiasareexamples.,這種方法的主要難點在于：可得的且非常復(fù)雜的預(yù)測藥物作用機(jī)制的方法既不能預(yù)測其毒性和副作用，也無法有助于預(yù)料在體內(nèi)藥物的傳輸特性和代謝途徑。當(dāng)然，在體外產(chǎn)生成功治療療效的藥物或藥劑學(xué)上的細(xì)胞效應(yīng)，這些都同樣重要。,Oneoftheprincipaldifficultiesinthisapproachisthattheavailableandverysophisticatedmethodsforpredictingdrugactioncannotforetelltoxicityandsideeffects,nordotheyhelpinanticipatingthetransportcharacteristicsormetabolicfateofthedruginvivo.Theseare,ofcourse,asimportantinproducingatherapeuticallysuccessfuldruginvitroorcellulareffectofthepharmacy.,由于對一種疾病(有關(guān))的生物學(xué)或生物化學(xué)(方面的知識)基本上無知，我們最好的努力也常常遭受挫折；于是，我們就傾向于劉易斯托馬斯在他的系列精辟文章之一中，所稱謂的“不徹底的技術(shù)”，即由于不能理解疾病的基本致病因素所采用的復(fù)雜而昂貴的疾病治療方法。,Veryoftenourbesteffortsarefrustratedbybasicignoranceofthebiologyorbiochemistryunderlyingadisease,andwearereducedtowhatLewisThomas,inoneofhisincisiveessays,calls“halfwaytechnology”inreferencetothecomplexandcostlymanagementofdiseaseswhosebasiccausesarenotunderstood.,而與大多數(shù)細(xì)菌性傳染疾病以及甚至像脊髓灰質(zhì)炎類某些病毒性疾病的治療方案的簡單性形成鮮明對照的是，對風(fēng)濕性關(guān)節(jié)炎、大多數(shù)惡性腫瘤和全部精神類疾病的治療都可歸為此類。,Thetreatmentofrheumatoidarthritis,mostmalignanttumors,andallmentaldiseasesfallsintothiscategory,andcontrastsglaringlywiththesimplicityofdealingwithmostinfectiousdiseasesofbacterialoriginandevensomeviraldiseaseslikepoliomyelitis.,雖然一些臨床藥用化學(xué)家和分子藥物學(xué)家一直帶著一些謙虛態(tài)度和難以隱忍的急躁情緒努力從事合理的藥物設(shè)計，但緩慢卻有前途的發(fā)展仍不斷帶來希望：在該領(lǐng)域的進(jìn)展比將生物和物理化學(xué)運用到人類和動物病理學(xué)（所取得的進(jìn)展）快得多。計算機(jī)輔助三維藥物設(shè)計的蓬勃發(fā)展有希望產(chǎn)生真正合理藥物設(shè)計的紀(jì)元（時代）。,Althoughsomepracticingmedicinalchemistsandmolecularpharmacologistsstillregardeffortsatrationaldrugdesignwithsomecondescensionandill-concealedimpatience,aslowrapidbutpromisingdevelopmentgivesrenewedhopethatprogressinthisareawillnotbelessthanintheapplicationofbiologyandphysicalchemistrytohumanandanimalpathology.Theexplosivedevelopmentofcomputer-aideddrugdesigninthreedimensionspromisestoleadtotheeraoftruerationaldrugdesign.,直到二十世紀(jì)六十年代早期，藥物設(shè)計還是基于長期經(jīng)驗、敏銳的觀察力、意外發(fā)現(xiàn)、純粹的運氣、和大量艱苦工作的一種直觀上的努力。發(fā)現(xiàn)一種臨床上有效的藥物的概率并不高，據(jù)估計為了生產(chǎn)一個具有實用（價值）的藥物需要合成3000-5000個化合物。,Untiltheearly1960s,drugdesignwasanintuitiveendeavorbasedonlongexperience,keenobservation,serendipity,sheerluck,andalotofhardwork.Theprobabilitiesoffindingaclinicallyusefuldrugwerenotgood;itwasestimatedthatanywherefrom3000to5000compoundsweresynthesizedinordertoproduceonepracticaldrug.,隨著當(dāng)今越來越嚴(yán)格的藥品安全監(jiān)管，這個（成功的）比例甚至更小，費用突升，也勢必嚴(yán)重延緩新藥的上市。藥物研發(fā)通常所采用的經(jīng)典方法是分子修飾設(shè)計已確證活性的先導(dǎo)化合物的類似物。其指導(dǎo)原則的范例是：在分子結(jié)構(gòu)中的微小改變導(dǎo)致其生物作用的微小、定量的變化。,Withtodaysmorestrictdrugsafetyregulations,theproportionsareevenworseandthecostsskyrocket,retardingtheintroductionofnewdrugstoadangerousextent.Theclassicalmethodusuallyappliedindrugdevelopmentwasmolecularmodificationthedesignofanaloguesofaprovenactive“l(fā)ead”compound.Theguidingprinciplewastheparadigmthatminorchangesinamolecularstructureleadtominor,quantitativealterationsinitsbiologicaleffects.,雖然這在緊密相關(guān)的同系物中可能是正確的，但這又取決于“微小變化”的定義。將兩個非常小的氫原子加入麥角堿的8雙鍵上，會消除它們的子宮收縮活性；但嗎啡的N-CH3取代基用更大的苯乙基官能團(tuán)替代后，則增加其活性近十倍。,Althoughthismaybetrueincloselyrelatedseries,itdependsonthedefinitionofminorchanges,Theadditionoftwoverysmallhydrogenatomstothe8doublebondofergotalkaloidseliminatestheiruterotonicactivity,butreplacementoftheNCH3substituentbythelargephenethylgroupinmorphineincreasestheactivitylessthantenfold.,而只將二乙吖嗪的側(cè)鏈只用一個C原子進(jìn)行延長竟導(dǎo)致氯丙嗪和現(xiàn)代精神藥理學(xué)的意外發(fā)現(xiàn)。1983年就有了一篇關(guān)于經(jīng)典設(shè)計的回顧性評述。,ExtensionofthesidechainofdiethazinebyonlyonecarbonatomledtotheserendipitousdiscoveryofChlorpromazineandmodernpsychopharmacology.Aretrospectiveaccountofclassicaldrugdesignwasprovidedin1983.,從這些隨機(jī)實例中可以得到兩個結(jié)論。首先，在構(gòu)效關(guān)系（SAR）研究中，只要其理化性質(zhì)仍未被探究或其作用的分子基礎(chǔ)仍未知，僅僅是有機(jī)分子的結(jié)構(gòu)改變是毫無意義的。在有機(jī)化學(xué)概念中，結(jié)構(gòu)僅僅是知識庫具有藥物活性的至關(guān)重要的大量參數(shù)的載體。,Therearetwoconclusionstobedrawnfromtheserandomexamples.First,amerelystructuralchangeinanorganicmoleculeismeaninglessinstructure-activityrelationship(SAR)studiesaslongasitsphysicochemicalconsequencesremainunewploredandthemolecularbasisofitsactionremainsknown.Structure,intheorganicchemicalsense,isonlyarepository,acarrierofnumerousparametersofvitalimportanceofdrugactivity.,從上述實例和無數(shù)的其他例子所可以得出的第二個結(jié)論是：定性新藥理作用的發(fā)現(xiàn)經(jīng)常是基于另外的單純系列藥物類似物上的不連續(xù)跳躍性（發(fā)現(xiàn)的結(jié)果）；即使采用相當(dāng)精密的方法，也很難預(yù)測。,Thesecondconclusiontobedrawnfromtheaboveexamplesandinnumerableothersisthatthediscoveryofqualitativelynewpharmacologicaleffectsisoftenadiscontinuousjumpinanotherwisemonotonousseriesofdruganaloguesandishardtopredict,evenwithfairlysophisticatedmethods.,Despitethegreatsuccessoftheclassicalmethodsofdrugdesign,theirunpredictabilityandthetremendousamountofwastedeffortexpendedhavenecessitatedthedevelopmentofmorerationalmethodswithamuchhigherpredictivecapability,inanefforttoelevatedrugdesignfromanarttoascience.,盡管藥物設(shè)計的經(jīng)典方法取得了巨大成功，它們的不可預(yù)測性和需要付出大量的無效努力使得具有更高預(yù)測能力的更合理方法的研發(fā)極為需要，并努力使藥物設(shè)計由藝術(shù)提升至科學(xué)。,Theapproachinvolvingthedesignofanaloguesofanactiveleadcompoundremainsunchanged,andtheexpertiseofthemedicinalchemistisasmuchindemandasever;however,theintuitiveprocessofselectingstructuralmodificationsforsynthesisbecomescircumspectinthisapproach,andmodelsbasedonmultipleregressionanalysisandpatternrecognitionmethods,usingverypowerfulcomputertechniques,areemployedasaids.,盡管涉及活性先導(dǎo)化合物的類似物的設(shè)計方法仍未改變，且藥物化學(xué)家需要的專業(yè)知識仍象以前那樣多；但在該方法中直觀選擇待合成的結(jié)構(gòu)修飾的過程變得周到全面了，采用非常強(qiáng)大的計算機(jī)技術(shù)的基于多元回歸分析的模型及模式識別方法也被應(yīng)用作輔助工具。,Itisobviouslymuchfasterandcheapertocalculatetherequiredpropertiesofnovelcompoundsfromalargepoolofdataontheiranaloguesthantosynthesizeandscreenallsuchnew,compoundsintheclassicalfashion.Onlypromisingcandidatesareinvestigatedexperimentally.,從大量新化合物的類似物的數(shù)據(jù)庫中計算其所需的性質(zhì)，比采用經(jīng)典方式合成并篩選所有這些新化合物，顯然要既快又便宜得多。只有有希望的候選化合物通過實驗才徹底研究。,Theresultsgainedthiswayareincorporatedintothedatabase,expandingandstrengtheningthetheoreticalsearch.Eventually,sufficientmaterialaccumulatestoaidinmakingaconfi