6P

46

= W* Ltr^ 0- d

rl

L,1 l,{r

% \,
Struc{ure-Activity Quantitative (QSAR) Relationships
Obj..tic: rh. drr.icql pbp.di6 of dtu$, in p5r! dict b $.r biologidl .ctivig. In.ddiliof,, useof decriplo6 ol physi@l th. rprliotid of mth.mltiol nodcls ro iEiFAdl6Fror !n.ly4.id predic!_l|Iygrgl$y up.n @mplnonof rh. OSAR l@ts. rh.;todat will b. nMr of |he diftcEnt phF @l prop.ni6 lnlI an0u@e biolosical tdivity, E. of th6e pbp.rtis nodeL lhar t laE the phvel in |h. devdopnfit of m$4ti6l prop6ri6 1obiologiol lctiviry, 6nd hoe rhc. m.thediql mdels dy b. c.d to ud4t nd dtug aclion

to+ L7krr
k^4'
: v)

,r' c , 0t / r b C 'r '/..=

t"It

{. tti-'' t) C-

Applications ofQSAR (Hansch Analysis) l) Llassl caoon 2) DiagnosisofMeohanism ofDrug Action series) 3) Prediction ofActivity (Congeneric 4) Lead CompoundOptimization

?oc.iP-&l

Sulmazole
oRc

/..-\

(..,t--/--\_/-

;'\

Syel.fltic lppo&h Io rcl.!. phylical poFrti* lo acovrtyth.r 's $pli6bl. for ! l.rg. tudb.r of cnmicat and biolosi@l sFtems

Krc '

Q""-;tn')
Ldou

U"Xkx

4k"
Hammeft lecfonic pammeteror substituent constant,o

?r,

Kx = tcoo-ltH*l4cootll

= log(Kxr<H) pox

dc unrcn'ad tid ionrzed aomt ofb.ndic Equ'trbnum b.t4d !fu tiedd|nn'onoI\ 'c'd

o Positiveversusngative Yalues
Pcidrcoj clclrn wjlhdl3eo& los (rVKH) > I dootii& log (K.4!, < I N.ertiveq.tctrn

Odho: minimt tdfdlbilily -. Mulipl. subGtitu.nts t conpound: ldditiv.lrqln.I on

the formsthat stabilize Example ofresonance negalivechatgedcarboxylate in p-nitrobenzoic acid

.+()
6"tt'?, ".''tc,

.v

"v,..

ethyl benzoates of Saponilication substituted

,t:F{-m,-L\-'i*
D Mqrertubi''j(do.dnpd sdei F'inE rop. indio'; iGti,n $ihd$ie ftsowJdF'fi!6kgbhi'bDnnglmlplfiv'k 1) tulid r ror uh*n .mFdN fos I

AG = -,lt?ln K
o, The Hammett constants. can be relatedto the free (ln via energyof ionization ihe vant Hofi relationship this K' constant, tothe equilibrium corespond caseo would to rclationships also be refededto for allowing Hammtt (LFER)). relationship energy as linearftee

Ester hydrolysisreactionand equationused Es to definethe Taft stericparameter,

oo

'a"-{

b-crh

"r

- "'"

('
0

' "*"
L

E,=b3tE-o*-bs

*.d -*=bi

*r=ffi.ry
Equation the molarrefractivity for

Considerationasymmetric of shape of groups molecules functional and

*+.- iRg\^
I t!r --Val@pst ricplmftts Solvet Aa6sibt. Surfice

Application ofQSARto biological systems; 1962

Considration ned crossmembranes of to

--- brain barrier Blood

(hvdroDhobiciN) LiDoDhilicitv

Eouationsfor the determinationof the partltlon 7r. parameters' P, coeflicient, andthe hydrophobicity

P=

n,=.g*

of Determination Partitioncoeflicient,P
ExprimenrallY Shaknask HPLC Reversd Phas Computationally Flagnntal constants, i Intmctionfactols, Fi

|' tP =t6gP' -

r Zt,+LA

+ - +-.

Exampleofa linearequationwheremultiple with are variabies usedto obtaina correlation biotogicalactivity (UC).

w(r)=*,u+t"'r+t"

Analysis Multiple Regression

Hypotheticaltraining sel of biological activitjes, hydrophobicitiesand sigma values

ll

l3

versus oro, including E leaslIndividualplots log(1/C) of analysrs squares

B A =.0 6 3 n+ I 20,f =0.?3

BA= 0 r 7o + 0 30,r ) = o49

lnfluenceofvariables(coefficients) the on agreement between experimental the and calculated activities

to of Application multipleregression set the training

r'z:0 90 o tr BA = -0.51 + 0.23 + 0.90, velsus f n BA = -0.63 + 1.2o, =0.73 and rr o BA : 0.37 + 0.30, : 0.49

Loo P versusbiologicalactivity ----1y=-*fparabolic Plot

Hansch equation

+ b gL = -7ro' + I(27t lko + k1

Exampleofan extended HanschEquationwhere the Taft steric parameter,E", has been included.
I

lqa=

-t ro' +kz,t+ \6 + kaE, l\ +

Advantages of Hansch analysis l, Useofdescriprors o, Esetc.) ftom small /n, organic molecules may be appliedto biological systems. B) Predicions quanlltative may be evaluated are and slatistically. C) Quick andeasy. D) Potential extrapolation: conclusions reached n4, be exiended chemical to substituents inoludd not in theoriginalanalysis.

DisadvantagesHansch of analysis
A) D6sipro6 G{uned for subsriruems b.ins srud,.d B) Litg. nunbs of conpounds r.{u'd (hrn,ns lel ror s h,cn pnrsr@o.mrorpommde' !trd b'oto8ior!criv,$ i!lvlilabt) 5 C) timrlllons *seDEd *rh usns sm nolecuredsrrplob,such ar i. hrtoR. on brctog'otirsl.B (i e d*.iproutmm phvrl D) Pld'rl prclonctron ofdrultar physiotog&t ondilroN {qr b IncruddIn mthffinol mod.l) E)PrdiclionslimiLd b rr!tuml cls! (@ns.neric jn6) F) TuDpglatio.tbeyond wru6 otd6c"proF 6ed In th. sudr r,e the C) Conhrion bdwe.nphys | d6n pro' Ford,frpte,hr I *" *,.**.on.ranon win ne,/eand. n6 rhe +l"d:11",:"[*

versusextrapolalions QSAR tnterpolations (SSS) SpannedSubstituentSPace Interpolative predictions: within SSS beyondSSS predicitons: Extropolative

( \.i

) -.r,\

an4.W-rlqqq.Mo39l -"._Free BA=>t-F-+k

'G"al,-]_

+ rilFiJ + k tog0/C)=IirFi,l +ri:Fi.2 +\rFi 3

n
Topliss DecisionTree for a Sulfa Drug

Craigplotofhydrophobicity versus o.","

plot Craig ofhydrophobicity versus Taft the Steric Term,E.

BatchwiseApproach
4.Cl:4.CH3:4-OCH3 tl 3,4.C1 A) Synrhsiz alr 5 anarogefor rh @mpolnd bing sludid. B) Dot6rnin biological 6clirlt ot 5 analogs and oblaanlh6 od6r ot lho acuvlly (highdr = l, loNr = 5) c) B5e6d on ordar from st6p B, lind wnich column in th6 fdlo\rdng iabl6 conspon& to lhat oftlr This idanlilia3 *lrich dg$riptor (i.6. r or 6) and ils 6ign ar imporlant for improving t Uologlcsl aclivity. D) Go lo lhe scond talls, idsnrit th row that conssponds to lhe . or o Elalionship d8bmlnd ln slsp C and ldontt ruDditulnls to add lo lh compolnd to fudtur inclas6 .divlry.

f qq qq

o?"???

10

for the Po{xrry ord.r for vatiousPanmter Depndncies BdFhwisc APPro8cn

on selectionsbasd pammeterdpndencrcs New substitunt fiom lhe Batchwisapproacn

+crJ.cr,i cror: lcr,: r.tt -ru

4-CH(CHrlr.{4lCHtrCHi 4_NrC:H!)2

tr,, I,rl(cl,l,,.r-n l.os, r-cx, rcHl 3{ri: I 4<cHJ: 4-Br:

pa|alnleft usedin QSAR lnvstigatiom Physiochemical

1l

for Analysis descriptors Hansch Alternate

p|! (limild ionizablo to comPolnds) -ahemicl shns trom NMR , quantum mscianid denvod propeniss orbilal gnsrgis HOMO and LUITTO eloclrDstaticpotntial around a molcriE (lik6 a magnelc ndd)

a- '

l--'.. .a

'r
/t

..':I

3D QSAR or CompartiveMolecularField Analysis(CoMFA) of to QSAR approach dealwith interactions taking molecules with their environment into account shape. 3D at Electrostatic Stericinteractions selected and pointsaroundmolecules replacephysical parameters normalQSAR in

T2