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DePartment WSI ComputerScience

Seminar:Algorithms in Drug Design

ws 03/04
LeadershiP: Jdrg K. Wegner

.T
Topic:

by: Presented Wilke Christoph

Abstract: As the lasl topic presented in the sern'fnar "Algorithns in Drug Design" afew of intiodtrced by earlier presinntion* a;e-revisited and applied to the the conceptsthat weredocking problem. First some of the chemical interactiofu reltvant A docking are reviewed. An outline of which concepts are relevant when transferring ligand-recePtorinteractions to a computaional leve! ari disc^sed- Various approaches are feasible and methods can be ofq, dqehing method the classif;edaccording n which approach they tal<e.A-san examp.le Simihr concepiire applied n ligand superpositioning toot FtqX.E des"iUa i, a"uii. by'iilioo! Flefi, alsodescribed in derail.

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Conteri:;

l lntrorluction 2 FIolec*Iar Interactions and Conformations

2.1 Molecular Interaction-s 2. ].1 Elecxostatic Interactions 2.1.2 llydrogen Bonds 2. L3 Van der lVaals Interactrons 2.2 PhysiochemicalProperties 2-3 Ligand Flexibilit5. & Conformation

3 !,igand-Receptor Eocking

3-l Requlrements for Docking 3.2 Rer:epfor Handling 3.3 Ligand Handling .l . -? I lfholc Molccvhz Hatlling . 3.J.2 Iragment Based l:fandlir4 3,4 Searching 3.4.1 Combinatoial and Geometic Searching 3. 4. 2 [ncrementa I Conslnrction 3.5 Stochastic and Energy Driven Searching 3-5.1 Monte Carlb TechniEtes 3. 5. 2 Genetic Algorithms 3. 5. 3 Memeric Algori thms 3.5.4 Tabu Search 3. 5. 5 Ma leculor Dynamics

3.7 Consensus Scoring 4 FlexX

4.1 BaseSelection 4.2 BasePlacement 43 Conplex Constructi,on5 FlexS - A Method for Ligand S*perpositinning 5.1 Base Placement aided by Rigtr'it 5.2 Increment*l Construclion 6 Conclusinn rnd Outlook

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1. Introduction A large part of b-iocbgmical interactions be grouped by the fact that they rely on shape can aQd_-Shape recggnition to-function.Examples such interactions iacludeenzymiicaialpis, of hollq-,o,le neurotransmitter receptors,other functional proteins-Should any of fggeptors, these mechanisms prove defoctive due to lac* , a. qig1'lilgg .4gp-nt or to be over -o-f causing harm as a result,thendrugsdeiigned speaifically t; eitherenhance oi firnctioning, subduea ceFain mechanismqay be calGil-foi.Drugs thii inhibit the productionofstomach acid have already proven to be effective to this approach of specificatly dealing widr thg caus ofa symptom. In funher attemptsto finding a target that can lead to the dvelopmnt ofnew dnrgs, knowledge of tbepcrite, site, to which a drug can potentially interact with can p6ve to be of- great value- Attempts 2t lnding 3 crtain functional molecule that can a c.g4ain interact with ilrleract wi0t the active site are-rtiided and driven by finding and matching sl1ap9 are guided shapeand lnti:raciion properties ol_q putatiy.gtigz-nd witt those available at th-e-,active sr6of a rq:cpnr. This is similar to comparingthe activeoidiliviiion site of a profein fo a lmkihat an be activatd by finding an appropriate key- l'he complernentarity d4 tlga4d and-a receptqrneed to.matclrort Severallevels.They qeed hav-E receptoi' need to. match.orf Severalleveis. Thev need to hdG lc-ri; cpmp cd;j;ntailrvllo tlmelteliry;io"fr nui ai in{eract. Computational methods need to be able to successfully handle biological and physiochqmical information, and irse the knowledge to make predictions about possible interactions- Several steps will need to be looked at and considered-

It is necessary to realize that rnolecr{e,s-afe completely rigid, but usually consist ofrigid not fu.Enentq qo4lteqte.d by bon4 that allow for different arranger-nentsin space of thq ^ti-gid fra-gments widr rcspectto eachother,while keepingthe samecompositionof the molecule"

2.1 Molecular Interactions [01

Looking at intermolecularinlggligp-qs oc.cClr-llrg a we rpgepJqr, see b.ejw.een ligaRd"andLhat theseare usuallyofa gon-cqvglert nature. Theseinteracqions arg.4o!ic9ab!eeidler as at@!!ens.,or rpulsions.niffiiio"i or moleculd iidr its- irqroJnaings can rg[qlt -h " variation ofits conformation.Throekinds ofinteractionsare tl4lical.

2. I. I Electrostalic

interactions

letostatic iod.*iio*

a isult of theil chargs- The interactions occur bet$-en two dolris ard are U" quantified by Coulombs Larv; "un

E:k' ql' q2/D' r

.E is the tssulting pu]si 6e diSa#-betueen *o-. factorof * : 3f2-

and r is ot 4tBqion, 4I and92 ae {re cbargeson each atosr' is a propcrtion*it"v and f ptw.*i';-sdii il ,s"dlctrr.oonstu*.

"t

2.t,2 !{ydrogen Bonds Tbese are ratkr v&aL.forces {csu{ting;-Fom ulellly Iequired is a bydrogen donor ftnd acteptor 'Jsributed,/ clcctr<-r dcusilies-

"{cr"np;;i; f,ffirfffr:ffi;'r#ry

j:*';l*Sff 'iF:9"" :X*;:*ru,m#"HElitrd'rfrff **o tbehv&ogen.is

to atom uahh

positirccha*ep partiar il *;r+*;;i Eii:llT..a 1'-:1l-tll .1,11lrf

Nr tt.-"N
6- 6+ 6i{-H-."'O

2.1.J lan der llaals Interaction! around an atom. The basisis thatorcr time no electron cloud is evr prfectlysymmetrical agnqt-"try inj[!.9lec1ronic charge aloun.d-analom actsthr,ox-gh-tectrostatic TLt:-eU&nt tp inte-ractigns inducp a complementary asymmetry in tlrc eleclibfr distribution around its t*.'i$Uo;n-q atoifi- fhe rexulling attBcfion btwen two atoms increases as they come close-d-istanges e}ecron closgr until they,are separatedb). the vdw lonEst d,istarce. {. clouds overlap and a skong rpqlslon occurs-

I
2J Physiochemical Properties

Beforc we can conclude to bioactiv-e comparisons, we first need to ob-ferve and classip p!ys-iS9!,e$isa!properties-For docking this concems modeling intermolecular interactions ofa ligand to apotential,receptor. Intermolecularinteractionsare divided into,,highly directional i.e- hydrogen bonds, salt bridges, and ino tessdirectionil interactions i.e. lipophillic interactions. Highly directional interactions are mcideled as inEraction centers and as interaction geonretries.Geometricaldescriptors show where a counter group might be expected.

rings or aromatic moieties. Theses forces are modeld as paired intermolecular interactions making. it possibte to approximate binding geometries, by meanqof discrete iriteraction points. G-au$ian.-,ftnctions may be usd to approximate the densities for various f)?es of pliyqiochemical properties. These includeJg,gal ty4-oph9_-bbity,p.artialalomic charges, and flbondingpoteritials. The center.of the Gaussian function is placed in the rcgion presumed to have the respectiveproperty- This may be an atom center or a region representing a certain proprtyThe Gaussianfunction is given by: : ae-Dt' I The height ofthe Gaussianis dependant bn fte parameter height a, and width D. The width is constant for all Caussians- The height gives a measure for the density of a certain 7 characteristicqf go-41. assigning'physiochemical propedies is to.later matchcorresponding groupi to The eachothr.

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2..3Ligand Fieribil;ty & Confornetions [ 1l The conforrnation ofa rnoiecule can be seen as snapshct of the siructurc ofa molecule at a\y instance. While th hI}4 g.qgigs ate usrally r-eslriqgd- to tile cnqs ditared by.the the connections betlveen hvo {igid ftagrnnts by single 'alence electron repulsicn modet, i!lorvs fc. .-dg,ee of fieedom. The ir:nform-ation of a molocule is def;ned by a set bq.ryJ3 , ol noion ong?cs betrveen rigid groups. Eich rotatable..bond can porentially spin i60

al{ possible conforraatians lies.in.the combin4oria}

in &grees, "nciri-" t.uo.ttt hedjro"ps aetn" ae torsi5i ar?ii. iba diflrc.ylry &germining
naFJleof the probbm.

Figure 2: Figure2.

Figure

2 slxt ls the freedomoi movemeflt that is possible with a singb bond. Here

with respect to the remaining molecule. Tbe bond angig b is dicbred by the valence electrbn repulsion. can CCnfo.mations result frcm lieedorn betrveen c;,clic bOnds,yiqlding -various Addj.ttq,n_"J .r.r!-conforlnations, i:e. chair, envelope, boat- Tlrc t".i&ie--d"Snces of Rc-edomresuit frogl th orientation androtation in spaceofthe r*'hole rnolecul'e.

3 Ligand-Receptor

Docking

In compfiance lo the idea that everv ,,lnck" has a,,key", rve can construci,searchand match ofthe ligand Th goal is tg useknowledge . variousmolecules ihe activesite dfa recePtor. to form a non{o\aleotly'bonded and the_rcplorto rnakepgg-rt ons if and how they will compx. l0 rvit\ a size of abo:r,! to 200 atoms.The is Here a liga,-nci a sinall organic nrole-cule can ofa ..."pio, ii i proteir,rtsuallv mrrchlirger sizethanthe ligrnd.Prcurcti.ns be ntade Tle ccmputational as to hoyl the ligand and receptoryrill interact to trrrn a cor'nplex. approach this is calleddoctrzgto

that It can be a-ssumed fgr a complex formed by a native ligand and its receptorcorrespond to a statein which the free binding energy is minimal. with dris knowledge the docking problem-becomes energyminimization task to find the lorveit free energybinding mode an and for'reCeptor a putativeIigand Difficutty is tinked to the fact that as a res!ft oforientation and different torsional angles, explosion.It are so manyconformations possiblefor the ligand, resultingi4 a combinatorial to ih;i;fore. nece's-a-ry develop heuristics and take corn{utational shod-cuts whre is _applicable. ir3.1 Requirementsfor Docking laJ^io-nal are the two components that typically make up a caglp^u$arching and s-coring. in atso a re3re-seritation bits and bytes of the receptor and the ligand is needed' {g9king. Usually a docking methodcan be classified-by the way it handlesthe receptoi an4 ligand andby the rypeofsearchalgorithm that is applied . that any docking method must explore the accessible f S"+onng refers to the fact ri co'4figuga,tionspace of the interacting molecules. Coal is to fin4 th -Qrienlation and of / conformation of the binding partners cgrresponding to the minimum of free energy

I uin,iing.

,fr"V pl"=#;Anflnumber resources.

of potential solutions resulting in need of giant computational

can approaches be classified: Two searclr ial gcrg4g,tric conrbinator or . stochasticor energt driven

It should be noted that most mod.gll Fearch strategieswilt often use a-hybrid of theseitrvo strategies,but they will be discussed scparately' All corrfigurations g.eleratd during a search process need to be evaluated and ranker!Scorine llij finctions ac-hievethis. Pre;Qq,edwould be the aqlq3l,free e4ergl as a score' fnii ii not-fpgally availa.blefgr computation, so scoring functions must adproxirnate, of binding fiee energieswith sufiicient accuracv.UrUally knOrvledge interactionenergiescan be classifiedzs eit-her force an! forcesflows into an assignedscore. scqJlng ftrnctions bav;d,or enpit'r?c/basedon a weightedsum of interactionsfeld

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3.2 ReceptorHandling of its to As meniionedprevicuslythe receptoris assurned be a p{otei-nWiih knowledge gire each atom of the composition und th.p., a stnightfonvard approach may be-to prove to be mugh too largefcr sucha ful! atomic Recep8ors .e.gpro, its orvn coordinaee. size' rvili a"pi"r.nt^tion, and the representation need-tobe reducedto a mQremanageable ttre original biological oi rvhile renrainingrpiesentative lbrn, size and fur,ctio{ralityof receptorto A first stgp is to limit.the search tie area surrcundingthe activesite. This is coinirton fq ligand-receptordocking- So blbr anv docking may ta'keplace' information nractice is lVith lwk this information mustbe available. lUqirt tf,e actlvi aorkinj siteoithe receptor lf comple-\esavailliite tbrorigh prio5liqe.hemit4l experiments, oi structural da'taof relatednletlods a1e regurl'gQ!o ylqld-.srch . information u#"i th" binding site is not available,_ pre' information. They are sooletirnes integraied ilto .docking Ppgrams as part of a pgjhe. ppqess_tr-rg Once information is reducedto o*ly the specific binding area.a !1U atomic reprcsentatron may be as rrlay slill be unfeasible-Insteadr an alaemative'ffoTetri: shapedescriptorsCombiningthe sear.chpsassigred.This is also morep{acticalandfISiqt for p-erlbrming veryeffective' rnayprove properties descrip6rswi*r ptrysiochemical geoiretric.shape Thesecaninc[uden4'!ecu|arsurfacecubesIl-lJorsphereimages[14]ofthebindingsite.In ixs"nce aromsare replacedby descriptorsbearing a certain physiochemicalpropfy' on based are regionana affinity po-ins. assigned, map is laid over tf,e search lopq rscoring energr.The grids are cakulated before the dockrogls-pertormed' furrctlonor interection ff,i" ,"trlf t" in a tgo-k-up'ti.lc ftr-pseudo binding affinities for the cth'r ation of !h irrtera-glioggrrglgiesoiscoring functions.during the dockingProcss'(AutoDock'trcM)" The receptor is comrnonly consideed and hqndig{ 4s-1 rigid prot;n structure' Wrile Lhis sonre of the computationalexpense' it provi&s a lirnitalion ir man;rca'sesThe various "^" conformationis often enoughnot the sum of its parts' but can assume -u" coliptex are It is evidentthatmany protein-ligan{,inlerac-tions- aclually&pendanton "onftr.rr*tions. a f ehanging,sh,ape,p6iromenor knorw as an induced t flAl tligactlre site

J-3 Ligand H:rndling of In contnst to the receptor, a full atomic reprsentation the ligand is pcssible.For the calculationof interaction energies'one could directly matsh the ligand with t'hebinding site. The different conformations that a ligand may assumeneed to be considered however, as the ligand may have an altemative binding conformation at th receptor than when by itself Two strategiesare available to handleand deal with ligands. One' consideredthq $ofe approach, is to observe and han{le theentire ligand, whereas a secondapproach, the -oecrii" dr4'tragmni based approaqh, is w-here ligand is dissected-

3.3.1 WholeMolecule Handling Wtth the whole molecule approach,tlrc-ligandis docked as a whole molecule . The ligand is considered to be rigid, and only the translationaland rotational degrees of fi-eedomare considered- This approach is co-tru!9.4..!q 944y-49c!oqg.co+putations. A variation was to pf .ab,e-aj time and then separatqly dock each corDp[te various conformations of a molepule ggngratedmolecule individualfy rvith the active siterigid base Fagrnent is defined and docked To incorporate some organization, u *-ton o!!y pnce. The dlffereniconformaiions'are 6en docked with the base fragmenthiming.a fixgd positioning between the ligand and repeptgrThe method is suitable for small sized moleculeswith li4ited degrees of freedom, reSulting in a small se-tgf discreet conformations. However,as the molecule size increasesso do the possibleconformations.One methodof dealingwith the many.conformationsis tc subjct them to energy minimizatiolr before they are dockedto..therecePtorconformation spaceis an adli-tional meth.gd ta treat ligand fle.ribjlity. It Saqglrag ligar-rdrgieg of $e ligand and interrrclecular interaction e-qgrgres reSUl.Fs.qg conformational ene. to bC'eviiuated- This is achlgved with molecularmechanics force field. The advantageis that a more exhaustive sampling of accessiblcconformations within the binding site is achieved.The disadvantage is a higher computaiionaldemand. Simpliging w\olg molecule handltng can be achievedby:rsing jntcanal.co.ordtnates*tlsead of Catesian coordinates. This hehs to redr49the amoun(-of.variables dealt witb when *ytt m. Coordinalqq ars. red-u-qd tq- bo.nd a"si'Ui"g the cbnformation of i-ot."ut* and'torsion angles. Since b-o.n4 lengt[rs, bond angles lp"pgth.and bo. angles ageusually -nd. is torsionangle. qujte rigid, the variable left remaining

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3.i.2 Fragttteat Based H.tndin.P into &ag lents. Fiagrnents can For the fizgment based approach ihe moiecu! is dissecte<i a ligid fasllion and then connected . This is simiiar to methocs be docked hdividually in on useCLr de-novo design. Most n:ethods described'later are fragment based approaches' 3-J- Searching As rnentioned a search rnethod shouid be abb to explore nrreentife configuratr'on space that the ligand and rcePtor may occupy- The g-o.alis to fin$ tlre energetic minimum of codbnnation a{d orintation of the p'urdiYe con4tex- The atlowed degrees of Aeedom can yieia a high number of potential sc{utions, therefore nreihods to redrrce and limit the search b found. 'fhe two approrches of dealing with searching are to ei8rer ,."u.""r**bty docking to a discret p-.oblarr that can be solved' or to..'sggC-chwith retnmulate the -ust search algorithmsstochastic

3.4. t . Conbinatorbl

and Geometric Searching matchiBg to actrieve

comtrinatodal or geomerric seaiching is based on s-[face o{desc{iptof

a shape fit between ligand and protein. For geomericliiscriotor based orocedures' the proportionalto the interaction energy' deeri; ofsurlace complrneRtarYis assumed
and between complerRenta-'y parts of the ligand and The key is to find correspondenccs 'last sguares! or a complte

such as minimization techniques can be implernentedrviahvariousdistarrce

Ceornetric shapes of interaction points cdn be matched,such as is done by $c base plac_ment ofFlexx (see sectionon FlexXJ-' A firahercxanrple is the origilal IX)CK melhodwhich lried to srpe-rimposeth,eligand onto a negativeqphereimage of the recepor site, widr thetrlp of a djstarce matching a'Eoritl}rrl' 3-4-2-Incremental Construction 13\ that-gopes lvell with dre combinatoriale}plosion of search possibilities is-tbe A stEategy ;ncrententuIcongnrclion techftklue. Also l<nownas,,mclror and groiv", the i$ea is to first sebqt _ard ptace a base fragrnnt- The previorxty disseced ligand is tlpn rebuilt confurxnationsare eliminated at the increnrentallyrvi.thin th acri\ srte-Mar}y ur".-:eiessar-}' to seleting iln appropriaiebase lreedsio be beginning- Special ccnsideiztion -siver ofl placedarerlependa',t the baseplacemeni as fiaerilent all further fragrnents

3*5.Stochasticand EnergyDrivenSearching A vierv of docking is that it is essentially an energy minimization and optimization problem. The native [6J bindrngtigand is assumedto correspondto the global minimal energy of the complex. Again exactenergy calculation is not possible,so that all nrethods and firnctions merely approximaiethe free binding energyThe functions should model the tee energy surface in an appropriate way. It is esrntial that the .glob.al minimum of a relative Free energy function resembles the position of the global rninimum on the real fiee enerry surfaces. {,. With an apptopriate energy- minimization function, docking can be perforrird optimizing . position . orientation . confbrmationofthe ligand
1::

by

Typical for the Aee energy of rhe complex formed by ligand and recptoris the uneven energy landscape and the high dirnensionalit)z rcsulting rn exhaustive searching, related and to ttre ru"gged ,,terain" is the occurrence of several local minima- This.presents new demands to the energ;rminimization functions. Solutions to cop with this are Monte Carlo and gepgtic algorithms. Sornetimes Tabu searches are also i$ill-iFd -tecbniques oc{asronally moleculard;rnamics usedto anallze dockings. are

3.5. I.fuIo nte Car lo Technioues The steps for Monte Carlo techniquescan be described as follows. Fi-rs1g-.1?!ld.9!n.groq!$9n of_thc -ligand. is. taken, i.e. 4rngom ya{iation in trarslation, rolation,.-aiiJ to*i*- n" methods depepd less on a certain starting point. A_{gq eperpr is calculated and assipgd for : tle r4itial pasition. A 19y._c9-Ir-{flr3!i-o_q ggqgrared by a turther random variation of a ip. parameter and thg._ggrv energy.is evaluated_@new)- Shori-ki tire-new co_nfiguBJi-o-rl a harrc mqre favorable energy (less ftee eney) than ihe old'- coiifigu;tion (foldl ttren it is and the searchcontinueswith a random variaqion of the rcw conf;glration. , .. -accepted S.trould a-newconfigurationbe lessfavorable,then the Metropoliscriteriondecides whether it is acceptedor not. The Metropoliscriterion is basedOna stochasticfunctien:

: exp{- (Enew- Eold)/kT)}

wherek is the_Bolzmann constant ris theobserved and remperature. prybatililr_ai!* rhe
then compared to a randomly gencrated value between l entl 0-0. The new confiEUiaiion -0 --is accepted if the randomly generared thanl p "alue-isG@i

Q.z

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I
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routirie resulting in Nlonte l'ruoenng a iea:perai"rre This orirciple can be ccmbine<! "vith rninimiza'tionstep resultingin Monte Carto tJ-.nnealing or with loal i:.i"''tr*'it minimization. vah'e . Forsimulatedannmling tl'e idtial tffpratBre is set to an artificially high sePSar pe{iorrned af'er a given amoun{ of Monte Cado and gradually{ow.ered, tenperaure. The foll'owing t fect can be notked: at a liven can be sampled"and et tLf, e.p"'.rtuos a broad regionlf 'configuration space due to ttle high eceptance probabiliry for bss be surmour'rted .n .g! burriio ""n favonble Placements., . and a configrrrai'on is I As emperatui ls reqr*ed this probability decreases more locallyoptimi.zed runs areneededin order random va{uesare incorporated' se''rcral Sime generated crtain strucnlral to make a gateFrlent about conveigence towalds a conformationthe rardom is for

3-5,z.GeneticA lgoriih ns fl7] as wc uavs rcaruvu C,eneticalgorithms are ry-Sqiy used fo1 docking- Oenehc a{gonmms! A ran4gln pgpld4pl i! gsnerated-.E?'ch ;; $ochastic ,o?timization rnethods-_ F".;;;t"

a Eaclchromosomeinchrcresnu@e; ;;;;eiiil "n*'no**i. a setof variablesr,r-rhe valueof a certainvariableof .o.rieroond

t9ryb," 'p::911-9f-!le'.T*:j: a potentiai l*-u". ii" popqhtion.onesponds,to "f of gctrcs'u4Jgerxs

ir*o For docking this transFates rhe foltowing srePs' to *re chmmosomes' t -) The variablesfor ranslation' rotation' an4 tor'siona{eencoded' ctossover)areperformedanda nervpc'oulationis (T.e. mutarions' i.i a.*C tig Th genotypeis decgSled.to phenotyPe' generated. "p"*A;; here fitniss coresPords to ttre interacti'oneriers/ i and as5ig*di-i Fi*r. is "iarat ofa dockingscoreis 4.) Th beslfitness then more like! to firrm new generations' when the popuhtion- bds reryb-eda canstant fitness or after a ;cts ;.i i;;i;;,ilt prca"ioei-numberof generations' a b-t Th. b"tt fimessat theerxl rpresents solution'

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J.5 S.Memetic lgorirhms A As a yariation, this algorithm combines genetic algorithms with a local energy minimization step- The algorithm samplesa certain frmtion of a new populationani subjects it to energ,y minimization.Tire resulting phenotype is mappedb4ck to a gnorype and the next population is senerated. This hybrid outperforms most GA optimization processs3.5.4.TabuSearch Tabu searching has also been a@ptedto.'v4r,iousdocking softr,raretools. With Tabu search, a _gndgmly generated positionis analyzed.by comprring it to a TabuJist This list conr4ins of previous solutions.Should the ryndomly geneiate.dpositioning not provide %gri.:q qrprificantly difiErent.arrangements drastically improve on the minimal erg4gy than or t-hosgalready tlre Tabu-list, Lhegeneration paramters are considered,,ta!u.. dLnd "t^'ed -in the previously visited areawill most likely to! be reyr$itgd3-5.5.M olecular Dyna mics [ | EI Molecular Dynamics is a courputarionally expensi'e rnethodthat is based simulatinsthe on actual binding processbyeximining and arialyzing the thermodynamicpf.rpe.tix oI the ligand and the receptor.Due to its ratherbxtehiive compurarionneeds, is liaited aoonly a it 'fev h,gb power systems,and is thereforenot relevant for docking and.is oniy siii6btJto dock known comolexes-

The above described methodsare inco-rporated into several programs. As mentionedearlier, a dockirrg technique can be classified by the way-it handles the ligand and receptor,and especially. by the search algoridrm applied. Listed below in Table I, adaped from [7] are examplesofeach searchmethod. Table I :
search melhod name

ADAMll9l, KI20l, FT.OC, LIGIN, QSDOCK,

construction

D-OC-( , Flexx [3], 4.0

Harimerlread

RESEAR [21],
Carlo minimizaticn algorithms

XP AuroDock1.0 , G-OLD[25j, WIN MDD nglvlD

PRO LEADS SFDock

abu Search

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3.7 ComemusScoring upon r}re avai{abb met'hods by combining Consensrsscoring [9] attemp{s to impl-o1eexjsJing sgo-r|ng -func1igrrsand algo;thms. A "slmr{ta'reous sroring and ranking is per&rmed using the rnethods integrated into sorneof ttre above mentioned stand alor softuare- Tire rs,.lhis that a irelter screeningcanoe peffofmed ard the h.its buad, plove to corsistent. Tbe only 4iddna!&ge $eing that for very specific tasks, :y tryiry be rngrre :neth@ witt iikely prforrn btter- Additiofial us may cor in whn on srflgle lunc[on ls unab{eiodeect a hit- flere iconsetrsus aproech naaybe nrore succ*sfi}L

4. FlexX I3l
' An availabb rool for perbrming a ligard-Fscptor docking with an Sg3g!4e'nta! constflrction +ochnique is. Fb+x. The ligand is cusidered and handled flexible ard i* .nnsirlcrerl to heiqi4 o"ii.sri' 14e scolns fq$nontaus. The ac{ive sile ;=dr. p*;# up oncompa.ring and a<{ding a infermofi:cuh( ilfieractions itrvolvedfun-irionusedrelies ' Threl nraia slepsma*e up tbe hlignurent !*haLgp; l.)Bae selection 2.Paseplacernent comrnrtion .3.Pomplex

ma4rally 'llx. b,tsesehction k pcrftrrncd intc<actiwly bLl&-u$er. ft needeto be sele-eled ()nce-it is slected *re E+Hiniry ligard.jsdi$e'igld a'te&!I- L-t44.!-h.nd, Lofn-lbe hgand fia-*" tigoo ir li"rgrnnted. 42. BaseFFacemDt to For rlrc baseplacemenr the .previous!" sekrted frrnnt Qeeds be 'P*tr*e-d;*u!l lbg.ggal ligand and the recPtor' A Illglgd galted inrrrctiqr pain gFqr-e of macffilondpg
- ::=::=3- " - - F - _- - Ee -

graI&icsis @d rccogrylgiq;r-.iqqo4pulel . poEE&ringuscd for p3!g.ern

'

for this step'

prope*iesre ,lsggrled to tb. basfr-rnent and fist, interacti<xpoina oiplrPio this, triangbs oF interactior poiql! ar connectd af the base the acrine *d 6il6,i;rg Ligrrer:t atd the agtive site. Thed6-a.'i cbatrlerized by the disi.ancesbetvreen comers. c?8 These.iis'"airces b-e-cornpacdto eaehother. The &conpatibility is giveo if the edgs b$gths of the con'esponding triangles diftr less th?$ a distance 6. obviously the corresponding coners of a tri.a*gle need to *lcilitate

ccmpatible interactions. algorithm is to compare and find all suitable 6The next step of rhe baseplacement hashing triangles at the active site of the rbceptor- A line segm.ent ccmpatible interaction are used which reduces the storage space of data structure and suitable algorithm to geometrically hashing triangles cubic vs'.quadraticThese i4teraction points are then mapped by superposing them onto triangles of corresponding interaction points of&e &ii?6 site. Two filters screen the transformations madefor validitY: to geometriesof tlre fragmentare chcked seethat l.) Angular constraintsof the interaction coincidewith those at the ligand site. centersat the receptor intgriction z$the placed fr4gment is checkedfor overlap with the receptor. to with respect because Similar entries are common in the listof transformationsgenerated, point of a triangle changes the the transformation of the fragment, changing one transformation only sligbtly, and one fragrnent triangl,e may match with severalpositions at tbe active site. To limit these before further. construction takes place, a hierarchical clustering algorithm, taliing rms (root-mean-square)distances into accoung is appliedTwo clusters with minimal deviation threshold in rms distance are iteratively merged and handled as a single cluster- With this, placemenB inside the same cluster are combined into one solution. The resulting interaction centers are then mapped again onto the interaction points on the recPtor. For small base fragments, occasionallyno triangular matches can be found, in which case an alteration of the base placement algorithm needs to be performed. This alteration matchesoails ofinteraction centenwith pairsofinteraction points43. Complex Construction O{ce a suitable base fragrnent has been selected, furthcr fragrnents may be added- Tlle a At fragrncnts are handled in a tree architecbre,where each ncde represents placement. are eddli iieraticin a fragment is addedfor all possible conformations and stmng overlaps rejected immediately- After each step the configurations are stored and ranked The ,k best configurations are kept and addedto in the next step-

. .'

S.FlexS- A Method for Ligand Superpositioning [2]

Lacking knowledge or insight abouta receptorcan severely limit &rrtheranalyzglgsteps. by Sho-uld qhance however,informationaboul an active or native ligand be available,then this can be utilized as a referenceliSand to construct and concluCe to a related a t superpositicin-tVith ligand superpqsitioningres Iigand can be modeledparts have been generate a list of potential ligandJigand alignm3nts. Sev-eral FlexS can merhod. A.n attractive feature of FlexS is the short ariapted-Eom ihe FiexX docking

- to -

cornputatlon time allovv'ing for screningoflarge databases' construction prc:eCure' lJ the center of FlexS's strategy is an Lqtenctive incr'ementa! (also as a cont;xuation of sirnilar to that of fiexible liganl-cleSg and de Novc <tesign plncement algcithms Fle::X). An anchor liagnrenf is sebcted by ihe user, t"ro difftrent then builds upon tire inen ui*errlpt to lace ihe base fuag:nent. Ii:creraental consh-trction possible' anchoror base fiagment and considen the confornlationafCegrees density functlons' Ph1'sicchernicalproPrtis arc assignedby Gaussian

5.1Brs Placrnent aided by RigFit JIt! pieced O.lrtgthe rFeflce ligand-Trvo For the baseplacement a rigid.mo'lecularfragroent-iS plrciment adaPtedfrom methdls are availabfe for'6is iiep Either i cornb-inatoiiqlbase at shidfo-iack certain.featr{s the ligand' a baseplacement fi,r* iki,;r ""."oinatorial RigFit alkrws rigidThis rlrethodcalied is n,,-"ri.of haseplacernentprocedure available' of rnoteculesacd molecular!4ments onto the rftrence rnolecule' Uodys.p.rpos;tioning physiochemkal propeilbs RigFit transforms the Caussian densitl' firnctio'ts of di&rent. Tlre phases are artificially neglecied' This simulates tire mokular ;i3- i.tti.i' "p*e. strucnlre. anallsh' A translztion replacerrrentopproach of X-ray crystau'og?PSic Ttri$*cars t* ttl:-Y1i is c...tiption of the nrolecule achieved' i"l"p..L", {fl.f-cjt: bal"",ce bei',,/"enaccurav and efiiciency is possible' al]owing a o"i-"'t[ il;;^;;; i'
.L - ^^|:-:-r:^- .-n!l.!i^_n.t ht'd^_ L?ndbd

a'-

t,arisfotm"ti.ttt., *peeding R.igFitup E" a fuctor of three' 5,2Incrcmcnlal Conslructlon

oPtimization in two iidependent steps- This makes it possibk to pefcrm a translational Fast Founer fairly quickiy- An additioml com6rtational slnrtcut is tdien b,v +pbing

Tl9" [qrg-rftqntat Aiter a srrccessful base placenrnt the fi?gnent can be extended' searchedfor is again hand'led in a tree sswture' The*lail ef?9e9 ftagment is ;;;;;; fragment' The o,ne* ooea bonds- TheL are bonds that harrcnot beenrnatird to a filrthr to.tlEse open bords at the are to matcired bonds th3r. closest.in -space d;4"";;;;;tJ fragarbnts' rigai- A scoring !;*ction is utilized'to chose.andplace the remaining t#**" similar in substrucnxe are ad6ci,'rvitb a biason keepingthe rernahring irnir"i r"&""" "rfernce r-norplik-eiy to ligand. T[r.dsa. is thar sirniliarly sizid molgcules are sizg-to the chamcbristics then are moiecuiesdiflererit in size' sh?r.e .-'
d

6.Conclusion lnd Outlool<

Virrious tncl.ltods availatrlc rnakcprcdictiorrs atc to aboutintcractions bclwscnligarrcls lrrrl rcccptors.Wltitc all of,thc nrcthudsg|J glglll li'lln!_1lU4jftft q1,-t!11cki1g rhcy srill -Ig*2 providc an irrsightinto liow cct'tainntolciulcs urayiirtcnrctwith caclr otlrcr'lMdt nrcthotls are continuallyinrprovedand adapted. Witlt thc advancenrcnts svailability cornputing and powcr iucrcasin.!.1 ntpidmtc tltlt of ilt tllc they arc cunrntly, sin4rlilications nttdc in ccftrur algorithnrs curr trc ,cplaccdfbr tlrosc calgtfl..r i,9!ua!.,!n!,j!!s!ia&s. !!'tC Scvcral of the principlcs uscd arc bornxvcd lionr othcl Dllrts ol' nril utilt tllc ics i1l!l htlbrrnltics, rtntlrtcconlinrrly soruc I thc-rrrcthtrtls,rrsqd-ixd o j1g rl'jvclop,efl-Q(tgli errrr lrt. il otllcj .lickls ot grrrrrgrrltiorrlI l1qlqlilptl*t!-solvllg.,l11.!js! !:9.1.t!fJ_l!1{/9!U.or-i!r11!!r .(!iq,j sluuristtv.

7. Sourcesnnd Ref'et'cnccs

tll

(brnrativc flcxibiliriit von Liganclcn inr Wirli.sro i!rrr". C. Schrvab "l(<,n llilcs Disscrration, Flicdrich-Al!-xatrdcr-Unvisity Erlaugcn iirrrbc Ccr:rlny. 20(ll. rg, -N C. Lcnrnrcn, T.Lcngalcr, C. Klcbc, "FLtlXS: A Mcrhotl lirr ljasr l:lcxitrlct.igarr(l Supcqrosiiorr"..,/.lt l al. Chcn. | 9911, l, 450245?0. t 4 M. Rarcy,B. Knrnrcr,T. Lcngaucr, Klcbc, .'A trast lrlsxit)lcl)ocking l\4ctlrtrl G. (i)nstr.uction usingan fncrcrncnl:tl Algolilhnl".l tlhtt-tjitl.tr.)90. 1()1.170:lS9 R.D. Cnnrcr, M.A. Poss, M.A.Hcrmsurcicr, T.J. Caullicld, lr,l.C.Korvala, lr,l.T. Valcntinc,"PrcsPcctivc ldcntitication Biollgicall: rcli\.c Sltllclulcslry lir|rorncr of Shrpc' Sinrillliry Sclrclring",.I A!c<l.Cin,tn, 199t. ./_'. | 9--19 i-1. .r9 'l'.N. llogcrr, .,Molccular J W.. Str.rrctrrr.c l)iss;rscrrrrryl t t g t : , r tt l .ll<lynrod, (MOSI)Alt):A ( hcrrric:rl Inlbr.nmlion N,lodcl I'o,/\ltt(,ltirtc Strrrcrrlt-ll;tsctl y *i c ' 1 1 l 'l t pttrlre'11y ('ltLtu. Con1nt..\i.i.l99i)..i'/. l6j_17-+ listirrralirtt",./. !n.1. Ivl'c' Niclihrrs-Plra'n*rcophorc.rrc D*rg Dcsig'". /lra;/rr'rtk,l ('rrctttLtittfitrrtuttit..t. Wiley, July 200.1, t(r87-t7 . C. Sot.itllr, M. Stahl, :rnd C. Klcbc, ...l-hcDocking problcur.., Il(rrlh(,t)t t)l Chenc i nJb n u ti c:,r, r Publishc Wi lcy, July 200-1,732: I lij . r.: | G. Klcbc, "F'rom S(ructumlscnonrics Drug Dcsign: Knorvlcdgc to l)iscovcry in Clrrystalloglaphic Databascs AssistLcrclI)isc"t'cryr*i,,.1 ti <ij.,,i,,,;u,u,,,-.. t ttrntlhtttl; ol'ClrcnrututiiutntrrtPublishcr: s, Wilcy , Ju15, 100_t i<r9_ZSi. f f

t2l t3l t4l t51 t6l 17l t8l

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te1
Il0l

tl rl tt2l tl 3l t r4l tt51 t l 6l tl Tl tl 8l lel t20l t 2ll l22l t23l 124l t2sI t26l I27l

St ttttsettstts orttt!':'\ J P.S.C'hrtril\on. I ('orkcy. N4.A Mtrrclio'W l' Wlltcls.''( (rl rl't,.l'irtq rlill;rh:tscs llllc(' ltit tltlcs liottt Mc'rho.t ti,r olltltirtiltg irrrprrrvctl //' 5l(x)'510()' rtlr tfirrrcrsir I sttttcltttcslrtlo lltrncills"'./llttl'( htut' t0lll' ()2(X|2' | I rr' l{l{)' "tl rv-Ii L-. .1. llcrg..l. I'vrtroczko' Str'1'cr iochcrnist li lt tiditiorr"' ligirtrtl Ir "l{iglrit: A ncrv appur;tclt srtlrcritrtposu Lcntrlcn. llill':r', l-cnglrrrcr' 1-501 Lltttpt tt.-,l ilcd Mol Dc.s'l99tt, /-?'49 nrolcculcs".,/. . 199{' l7' I l 7- l l'i ' .lt Kuntz,Mcng,Sltoiclrct' r'.C,/tc'ar./lcs Kirn,.,l.itlo!.Bio!..l99l ' 219'79-102' Jrang, lvlol'lJiol'.l99tt' ?'/'r'459-;177' Nttssirtov'J' Lirt, Woll'sotl, l:'ischcr, J Walkinsharv. lvlol Eittl',ll)98' 277'1J9-!66' Taylor', Burkhard, 'l'ltctttrt'd atu ytt ics: lttlr'tclttctiott in Totrov.Abagy:tn R.B. l{all;r;ciJ (r03-624 2001 "'DrugllcocPlor andeppticalons,Wilcy, C'hichestcr' , Chau ' I993'-16'2|42-2l67' Mirankcr,Kaqrlrrs, tulatl. Caflisclr, ',1. I02,lll2(]-1055:"/a.gtrr"(ht'rtr'ltl' 1990, Clham, Attgctt'. []ctcndscn, vanCunslclu, Etl. Engl. 1990,29, 992- 1023. 4, M itzutini. Tonrioka, lt^i,,!. Mol - 8 b|. 199 243, 3 10 -326' Krttrtz.' (otul,ttt./lit!<lIktl l)r"i ' 2(l(ll' /'t"lll-42Ii l')wing, Mrkintr,Sliillnlalttrt 'J Olson.Pt otcitl.1990' ,9' 195-202. Cootiscll, Hart,ll'cad'I'l.Q|i|N.l992.|.j,206.222. ( /-i"{.15--l5l lr'h l.iLr, Wrrrrg,./. r;rttlttrr.-.1i1<l l)L's lt)t)t). ' I'roc. Null Aaul Scl U57' l99lt'9-i,80|I-E0l5 Schcruga, Tx)ssct, Aitlcl l,k Brbl..t995. ?J't.4i-51 Willct, Clcn..l. C<;n1tttt. Jones. 2000''l /, I 7l- l9 I . /)rrrcirrs, Bunrctt, Taylor', Prol(ir.!' l99tl. -j. -167-lilil' EldddSlc'. Baitcr, Munry, Clark.Wcsthead,