molecular modelling probes

8/6/2019 Molecular Modelling Probes

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Blodnri(nl todety trnnlrdtotrr 200:l)Votlrrc i, p..r 5 ha,Fr:v @Molecular odelling robes:ocking ndscoringR.T. roemerr[ompltatiooalSciences,epa.lmefitf hemistry,harmncia,Vinleasleur0,20014 (vianotv1t),aly

AbstractAgeneralntroductionomore(urarodelinge.hniguesn heareaot protein-rigandnteradionssgiven.Methods overedange rom binding-site ialysis o 5tatirticalreatmentof sersof ligands.he mainfo(Us t thir paper5on docking nds(oring, tteran outline l themain on(epts,wo spe(iric ppli(ationexamplestegiven.

IntroductionOver the pasr 15years a variety of applicatioru andrechniqueshave been developed, in order to perform rz silto cir t_latiom of proteio-ligand inreractions. n this contexrone canthink ofa variety of areas,which are outlined in Fieure 1 Infie remainderof the introduction, a very brief ovlwiew ofthese echniques s given [l], The subsequentheadingswillthen ocuson rhc ropics ofdocking and scoring,whicliare ofparcicular nterest n current drug research.For manyapplicarionselated o crlcularingprotein_ligandmteractions it is necessary o have the protein structure(s) ofinterest at hand. If the structure is not available,ooe c* .esonto rhe cechniques f prorein-structure prcdicrion [2]. Mostc-or4spdy applied are ,threading and homology modelling[3,4].Duringthreading - or fold recognition * ."".r"^.rriis.made whether a given amino acid sequence s compatiblewith one of the structures in a databaseof known folds.Homology - or comparative - modelling relies on a clearrelationshipor homology between he sequence f the targerprotein and at least one known structure,Be it from experiment or ptediction, once the three_dimensional sruoure of rhe protein of interesr has beeoobraincd, t canbe analysedusinga varicty ofcompurationalrechnigucs. f_rhc uncrion of thc protcin is unknown, ir maybe mporrenr !o search ts structure for putarivebinding sitcs[5]. These,bindingsites cansubsequendybe explorcd flr thebindingof selectedmolecules,or they can be comparedwithother,.knowrL binding sires. n many cases he binding site(and he funcrion of rhe protein) is known by ..f.."n".-1..g.me protern can be assigned o a prorein family with knowntuncdon), or the protein has been co-crlstallized wirh aligand.An ana.lysis f the binding-site characcerisdcsnd/or.

the interaclions with a given ligand can lead ro importantinsigls for the design of novel ligandsor the docking of anumber of puarive ligand molecules[6,7].. . The design of novel ligands or a given binding sire is ofnlgh lmportance n current drug research, nd it is normally

referred to as de noao or ab initio ligand design. Manyprocedureshaveappearedwhich accomplish rhis task in aoautomated ashion [81.Normally, theseprograns arlempr rogenerare oovel ligaods rotally from scratch, or they. sr"rrfrom a given ligand and rry to modify ic in such a wavrhat its inreractions with rhe arget protein arc improred or-oprimized [9].Somcrimesalfinity dara for a ser of prorein ligandsarcavailabli, buc it is noc possible to obtain a reliablereceouorstrucrure.Forexample, experimentalsrrucrures f mernbranebound or embeddedproreins are hard to get and even goodmodel sructures are difficult to obtain. However, ir wouldbe desirable o perform some kind of rarional manipulationof the ligands, with. the.aim to design igand molecrrles harorno n an mproved ashion.Most commonlyapplied nderthesecircumstances re.indireicr, or ligand_basedmodellingtechniques,such as pharmacophore modelling and eSAi(quanrrtalrve structure-acriviry reladonship) approaches[10,11] .Docking of small molecules to rcceptor slructures hasbecome increasingly imponant in rhe context of drugdiscovery [12-14]. Over the past few years a number ofmerhodshavebecndcvcloped orpcrforming (reladvely) astprcdicrionsor a scrics f molcculcscgardinghcirabii iry obrnd ro a protein binding site [15J. n the foliowing thesemethods are described in some detail, followed bv- someexampleapplications.

Gene.ralefinitionof small-moleculeoo(KtngGenerallypeaking,ockingscarried ut usinga compurerprogram. n 91{g to dock computer-geoeratedepresent-ationsof smallmoleculeso a receptor or ro a user_definedpartrhereot, .g. heacrive iteof anenzyme),ollowedbyevaluation_ofhe molecules irh respecto co-ple-enurityln terrns t shape ndpropenies,uchaselecrosratics.oodcomplementariryof a molecule odicaresharthemolecr.ilespotenrr-allygoodbinder. heourcome fa docking xercisenoimally ncludes omesort of affinity predicriooor rbemolecules.investigared,ieldinga relariveank-orderingfthc docked ompounds ith respecco affiniryXeywofilt: dlli ity t rddtoq .nde$l tntelaction, orepediction.Albr.vhtoni uted; CAtl ddonir inhy&.re ; plp.t0 |roreifl tyroritredo5phatile-lt; rfi,high.lhroughput(|ean.

4ro0! slothemiGt !{tery


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lntermole.ular tso.ialionr n 20.nd lD

Figu.e1| De.isionree or (hoosinghe appropriate ethod or modellinq rotein-ligandnteta(tiontQSAR,uantitativetructurectivityelationship;8DD, tructure-basedfugdesign.

Benelits ndapplicationsIf the affinities of molecules o a reccptol can be predictedwith reasonable ccuracy, here are obvious benefits fromthis approach. Onc of the buzzwords in drug discovcryof rhc recent years has been 'virtual scrcening'; in thecontexr of docking this implies docking and scoringof largenumbersof moleculeswithin a relatively short time frame[1'6.l. hese moleculescould be a databaseof compounds,either proprietary or commercially available, or a largelibrary of virtual molecules designed on a computer.Only the compoundswith the best-predictedaffinities aresubsequently electedor synthesisand/or testing.Providedthe selction odtarnsa argeproporrion of activemolecules,'enrichmenr' has beenachieved,and significant amounrc o{t imean dmoneycouldbc saved 17].

Pose redictionersus ffinitypredictionTechnicallyspeaking, he placement of the molecules n theregionofinterest (e.g. he receptor-bind ng site) s referred oas'docking', whereas he pred-icrionof affinity is referredro as scoring',Alrhough termcd docking prograrns',hcprograms uscd nowadays are designed ro carry out bodlrasl


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, : {!t|*ltrEr*Ji r

ProteinStructureModeltJf.:lj DrugDiscovery

Genomics& B oinformaticsDw 12.13.02


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' l 'hcpast ovcrar caru avc cc ' . shit Jionr honrorc ra,.liti.nar.wc t chcrnistry"drugdiscovery roccsso ..lnslllco,' roccsscs,hich akcadvanlagcf thcdatamanipulationndm.lcoularnrodcling rowcss I nr.trcr' compurcrs.r'hcrcsLrrtingimplicationsor drugdiscoveryanddevelopment reunprecedented. hire traditionar,top-down rugdevelopmentechniquesookas rongas40 ycars o rcturna viabrcdrugproduct rom abasicunderstandingfthe targetprotein's unction,morccurar omputer-basedechniquesodayallowa drug o be developedn only tnreeyears,as was hecasewith the chemotheraputicgentHerceptin@.1Structuralmodelinganddatabasecreeningn particularhashada similarlyprofoundaffecton alternative rugdiscoverymethods.The humangenome rojecthasunveiledabout30,000uniquegenes, nyof whichcouldbe apotentialnew drug arget.Furthermore,t is estimatedhat heremay bebetween 0 and r00 slightvariantsofeachgene,effectivelycomplicating roteincharacterization.2unently,very few of theseknownproteinsequencesreactuallyaccompaniedy a known3D proteinstructure, utthe gap s closing' Frequentlyagged s "the majorchalrenge fthe postgenomicera,,,3the ranslation fsequence ata o structural nowledgehasgainedsignificantground nthe astseveral ears. Consideringecentmprovementssonly the ip of the ceberg,structuralmodelingandcomparisonsppearo be thenext,significantool for moreefficientandprofitabledrugdiscovery.

ComputatinalStructureModelineMethodsSince he first proteinstructurewasdeterminedn 1g57,structure nalysis asevolvedfrom simple determination o modeling. X_raycrystallographywastheprimarymeans y whichaphysicalmolecular tructurewasdetermined xperimentalry,ut thismethods not widely applicable only one n twentyproteinsbrm usefulcrystalsorstucture studies, ndsome,especiallymembrane roteinsandproteincomplexes,ormno crystalsat all.a Ratherthanforcephysical sfucture determinatronmethodson acompoundn anattempt o yield largervolumesofsfuctural information,science astakena morepractical andrationarapproachhrough computer-based tructue modelinpintegmtedwith physicardata. proteinfordingcannotbe predicted rom sequencerone,-


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however,as herearesomanyvariables o take nto account hat mostadvancedcomputers re oo slow to achievehis n areasonablemountoftime.Homologymodelingand hreadingechnologies, hich rely on alreadyexistingknowledge f 3D proteinstructureso inferstructurerom sequence,avebeenused nlieuof autonomousoldingmodels.Threadingmethodologiesreused n the rimitingcasewhen here s insufficientnfomrationor regularhomologymoderingo be possible.The naccuracyn the nputs esultsn imprecisionn the output: hreading ieldsmultiplestructure redictionshatsupplyausefulpictureofhow aproteinmaybestructured nlywhen aken nto accountogether.Overall, houghhomologyandthreadingechniquesreuseful or basic irnctionelucidation,heyare oo approximatefor drugdesign.

Anothermethod or structure nalysis, MR, combines hysicaldistancedeterminationsith computationalefinements.unfortunately, his technique ecomeslesseffectivewith larger argetmolecule izes.Dynamicanalyses fprotein structurealso epresenthenew front in computationalmethods.Rather iran ocusingsolelyonthe 3D structure f a protein, t is increasingly ommon o modelstructure ariationwithtime,or 4D structuremodeling.This is achievedhroughsimulationof thechansesnmolecularmotionsandproperties f a proteinover ime.

Structuremodelingmethodsarebeingcontinuouslyefinedandnow approachheaccuracy evelsof moretraditional methodsof structuredeterminatioo. &!qo_!_ogy_methodsarenearingX-ray crystallographyresolution: in a compansonbetween he X_ravcrystalproteinsfuchrresand hehomology-derivedtructures f SanDiego_basedStructuralBioinformatics nc., t was ound hatabout960% erewithin 1.5Aor better,and98%o erewithin 2.0A. Although heaccuracy f the modeldeclinesassequencesimilaritydecreases,omologymodelingmethods restill effectiveat as lowas 20yosequenceimilarity. At SBI-Advanced echnologies, Denmark-based ompany,secondarytructure rediction rom sequencesinghomologymodelinghasanaccuracyof about80%0.5hreadingechnologies, n the otherhand,are essaccurate threadins


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prcdictcd tructurcsillcr liorn hcX-raycrystallographytrusturc y 3.2A_ l7 6A,whereaswo crystalstructures ouldtypicallydiffer from I 5A - 1.gA.6A drawback faoth methodss that heyaremosteffectivepredictinghe proteincore t i"tu." ur" I"r.accurateor surface tructures, hich s wheremostprotein nteractions ndactivitytakesplace.

Modelings tselfvery lexible, ndcharacteristicsfthc sunoundingsrneighboring ompoundsanbeapplied o themodelingprocessn order o predictstructuren a particurar ituation.This flexibility is plainryabsent iom physicalstructuredetermination ethods:X-rayandNMR structures lone epresenthebehaviorof aprotein n a specificenvironment ndmaynot accuratelyeflect eality. protein-proteinandproteinJigandnteractionsuchasdockingcanalsobemodeled,an exceptionallydifficult tasi becauseroteins hange hapen responseo the presence fanothermolecule.Structuremodeling s alsoextremely seful or predictionof protein unction.Because tructure ictatesmolecularbehavior,t canbe directlycorrelatedo acompound's ctivityand unctionwithin rivingsystems.This reasoning anbe racednreverse, o hatwhena compoundwith a particular unction s sought i.e.binding o aspecificmoleculewith aknownstructure),hedesiredunctioncanberelated ostructure,which s in tum predictedrom sequence. his enabresotentialnew drugs obe dentifiedbased n sequencelone.

BenefitsoDrusDiscoveryOut of the30,000humangenes nown,drugson the market oday argetonlyabout500differentproteins.THence,hestructural nd unctionarunderstandingerivedthroughmodelingof thistremendousmountof untargetedroterns anbeexploitedordrugdevelopmenturposes.Structure-basedomputationalcreenings the mostefficientmethodofsortingout potential drug targetsor potential new drugs o intemctwith a given target. Forexample,whenahigh-qualitystructue ofa targetprotein s available,t canbeused ocomputationallycreen roteinandsmallmoleculedatabasesor a compoundhatbinds

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On theotherhand, heefFrcientnterplaybetween atabases aybe a mootpointoneday f computing owerwas ncreased uch hatstand-aloncolding modclswouldbepractical. f computing dvances ontinue o move at a rapidpace,with performancedoublingevery 8 months, hen t is estimatedhatby 2010 hepredictionofthe foldingpatterns f simpleproteinswouldbepossible.12 owever,his ime span s too long toignore he advantagesfintegratingphysicalandmodeled tructureshat are availabletodav.

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