Drug Design

B. PHARM 6TH SEMESTER DRUG DESIGN. FACTORS, QSAR, DRUG DISCOVERY, DRUG DEVELOPMENT, VARIOUS APPROACHES FOR DRUG DESIGN, PARTITION COEFFICIENT, HAMMETS EQUATION, TAFTS STERIC PARAMETER, HANSCH ANALYSIS

1. PRESENTED BY-
SIDDHISHRIGIRIWAR
NAGPUR, MAHARASHTRA, INDIA
[email protected]
NAGPURCOLLEGEOFPHARMACY
MEDICINALCHEMISTRY-III
DRUGDESIGN

2. CONTENTS
➢DRUG
➢DRUGDESIGN
➢FACTORSGOVERNINGDRUGDESIGN
➢DRUGDISCOVERY
➢DRUGDEVELOPMENT
➢TYPESOFDRUGDESIGN
➢LIGAND-BASED&STRUCTURE-BASEDDRUGDESIGN
➢VARIOUSAPPROACHESINDRUGDESIGN
➢BASICCONCEPTSOFDRUGDESIGN
➢QUANTITATIVESTRUCTURE-ACTIVITYRELATIONSHIP
DRUG DESIGN

3. DRUG
DRUG
Drogue
Frenchword
Means
DRYHERB
PLANTSOURCE
DRUG:
➢Adrugisasubstanceoramoleculethatisusedforthepreventiondiagnosis,cure,mitigation,and
treatmentoralleviationofitssymptoms.ofcertaindiseasesORabnormalconditionsinmanand
animals.Thesearethatsubstancesthatchangeormodifyaperson’smentalorphysicalcondition.
➢Itgivesatherapeuticeffecttothepatientbyinhibitingorinducingthefunctionofabiomolecule.

4. DRUGDESIGN
DRUGDESIGN:
Thedrugisplannedorarrangedinsuchawayi.e.inventiveprocessof
searchingfornewmedicationsbasedontheknowledgeofabiological
target.
Drugdesignisanimportantpartofdiscovery.Itisasystematicapproachto
findingorresearch,selection,andoptimization(mosteffective)ofdrug
moleculesbasedonmolecularinteractionsbetweendrugortarget
proteinoritsphysicochemicalproperties.
Inthepastfewdecades,theresearchanddiscoveryofnovelmedicinalcompoundshasstopped.This
trendindrugdevelopmenthasincreasedduetotwovitalfactors;
➢firstisthestrictempiricalandrationalapproachtodrugdesignand
➢secondisthehighstandardsofsafetyandtherapeuticefficacyalongwiththeincreasedcostof
research,development,andclinicaltrials.

5. DRUGDESIGN
Drugdesignexplainsthefollowing:
1)Effectsofbiologicalcompoundsbasedonmolecularinteractionintermsofmolecularstructures
orphysicochemicalpropertiesoftheinvolvedmolecules.
2)Variousprocessesbywhichthedrugsexerttheirpharmacologicaleffects.
3)Mannerinwhichthedrugsspecificallyreactwiththeprotoplasmto
produceapharmacologicalresponse.
4)Mannerinwhichthedrugsaremodified,detoxicated,metabolized,oreliminatedbytheorganism.

6. 1.Smallertheexpenditureof humanandmaterialresources involvedintheproductionofanewdrugof a
particularvalue,themoreviabletheprogramdesign.
needtobeestablished
2.Experimentalanimalandclinicalscreeningoperationsofthenewdrugs.
3.Relationshipsbetweenchemicalfeaturesandbiologicalproperties
retrospectively
4.QSARvariesbasedonthenatureoftheevaluationofstructureoractivity.
5.Thetrendtosynthesizealargenumberofnovelmedicinalcompoundsforexploratoryevaluationstill
succeeds,thusreflectingthecreativeauthenticityandfunctionsofanindividualizedexpressionof
noveltybyamedicinalchemist.
6.Substitutingthemoleculewithfunctionalgroupsthatdonotnecessarilyresemblethemetabolites
7.Diseaseetiologiesandvariousbiochemicalprocessesinvolvedproveuseful
FACTORSGOVERNINGDRUGDESIGN

7. Stage2
Stage1
Stage4
DRUGDISCOVERY
Stage3
Drug
Discovery
2-5years
Preclinical
Developments
1-2years
Clinical
Development
5-7years
Regulatory
Approval
1-2years
100Projects Millions 1molecule

8. DRUGDEVELOPMENT
Numberofcompounds
5,000-50,000
250
5
1
BasicResearch
DrugDiscovery
PreclinicalResearch
ClinicalResearch
ApprovedDrug
Drugdevelopmentisthe
processofbringinganew
pharmaceuticaldrugtothe
market
compound
identifiedthrough
oncealead
has been
the
processofdrugdiscovery.
Theentireprocessof
bringinganewdrugto
market.Itisanintegrated,
multidisciplinaryendeavor
thatincludesdrugdiscovery,
chemistry
pharmacology,
safety
and
non-clinical
testing,
manufacturing,clinicaltrials,
andregulatorysubmissions.
5STAGESFORDRUG
DEVELOPMENT:
PostMarketingMonitoring

9. TYPESOFDRUGDESIGN
DRUGDESIGNTECHNIQUES
LIGAND-BASEDDRUGDESIGN RECEPTOR-BASEDDRUGDESIGN
Pharmacophore
Model
QSAR
Molecular
Docking
DeNovoDesign
VIRTUALSCREENING
Identificationofthatmoleculethatbindstothetargetedsiteorreceptor

10. Ligand-BasedDrugDesign:
LBDDreferstodrugdiscoveryeffortsintheabsenceofanytargetstructuresandinthe
presenceofchemicalstructuresknowntomodulatethetarget.Themostpopular
approachesforligand-baseddrugdesignaretheQSARmethodandpharmacophore
modeling.QSARisacomputationalmethodtoquantifythecorrelationbetweenthe
chemicalstructuresofaseriesofcompoundsandaparticularchemicalorbiological
process.Alsoknowndirectasdirectdrugdesign.
Structure-BasedDrugDesign:
SBDDisaniterativeprocessanditproceedsthroughmultiplecyclesleadingan
optimizeddrugcandidatetoclinicaltrials.Generally,adrugdiscoveryprocessconsistsoffour
steps:thediscoveryphase,thedevelopmentphase,theclinicaltrialphase,andtheregistry
phase.(SBDD)usescomputationalchemistrytoolsinwhichthestructureofaproteinis
usedasthebasistoidentifyordesignnewchemicalcompoundsthatcouldbindtothe
targetresultingintheinhibitionofthetargetprotein.SBDDusesthe3Dshapeand
structureoftheproteinasthebasisfordesigningnewdrugs.Structuresdeterminedby
NMRspectroscopy,X-raycrystallography,andhomologymodeling.Alsoknownasreverse
Pharmacology.
LIGAND-BASED&STRUCTUREBASEDDRUGDESIGN
LBDD SBDD

11. 1)QuantumMechanicalApproach:Quantumorwavemechanicsinvolve
someessentialprinciplesderivedfromfundamentalassumptionsthat
effectivelydescribenaturalphenomena.Quantummechanicssatisfactorily
explainthepropertiesofprotons,neutrons,andelectrons.Theelectronic
featuresofthemoleculeselicitchemicalalterationsandformthebaseof
drugmoleculephenomena.(Howatomicparticlesexistandinteractwitheach
other)
2)MolecularOrbitalApproach:Thisapproachisbasedontheassumption
thatelectronsinmoleculesaredirectlylinkedtotheorbitalsengulfingtheentire
molecule,andthisstatesthemolecularorbitaltheory.
Themolecularorbitalapproachshowsdependenceon
electroniccharge(asprovenbystudyingthreevolatileinhalationanesthetics)
andonmolecularconformation(asstudiedconcerningacetylcholinebyparameters
likebondlengthsandtorsionalangles.
VARIOUSAPPROACHESINDRUGDESIGN

12. 3)MolecularConnectivityApproach:Thisapproachestablishesthe
presenceofstructuralfeatureslikecyclisation,unsaturation,skeletal
branching,andthepresenceandpositionoftheheteroatominmoleculeswith
aseriesofnumericalindices.Forexample,intheSARstudyofamphetamine-
typehallucinogenicdrugs,anindexwasfoundtopossessacorrelative
factor.Themolecularconnectivityapproachhasthelimitationsof
electronegativityvariancebetweenatoms,andthenon-distinguishableentity
ofcis-transisomerism.
4)LinearFree-EnergyApproach:Thisapproachestablishesthelink
betweenproperselectionsofphysicochemicalparameterswithaspecific
biologicalphenomenon.Thiscorrelation,however,doesnotallowadirect
interpretationaboutmolecularstructurebutoffersacluetowardsthe
selectionofcandidatemoleculesforsynthesis.
VARIOUSAPPROACHESINDRUGDESIGN

13. VARIOUSAPPROACHESINDRUGDESIGN
5)DesignofAnalogues:Aalougeisusuallydefinedasthemodificationofa
drugmoleculeoranybioactivecompoundtoprepareanewmolecule
showingchemicalandbiologicalsimilaritywiththeoriginalmodel
compound.Analogsarethesesubstancesthatarealreadyinuse.Theycan
besynthesizedbychangingthepositionofthesubstitutiongroup.
ForExample-Tetracycline Oxytetracycline
6)DesignofLeadcompoundandLeadDiscovery:achemicalcompoundthat
showspromiseasatreatmentforadiseaseandmayleadtothe
developmentofanewdrugduringleaddiscovery,anintensivesearch
ensuestofindadrug-likesmallmoleculeorbiologicaltherapeutic,typically
termedadevelopmentcandidate,thatwillprogressintopreclinical,andif
successful,intoclinicaldevelopmentandultimatelybeamarketed
medicine.

14. BasicConceptsofDrugDesign
Successfuldrugdesignisamulti-step,multi-disciplinary,andmulti-yearprocess.Drugdiscoveryisnota
predictableconsequenceoffundamentalbasicscience;drugdesignisnotjustasimpletechnologyof
generatingdrugsforhumansbasedonbiologicaladvances;ifitwere,muchbetterdrugswouldbe
availablealready.
Medicinalchemistryisasciencethatprovidesamolecularbridgebetweenthebasicscienceof
biologyandtheclinicalscienceofmedicine(analogoustochemistrybeingthecentralsciencebetween
thetraditionaldisciplinesofbiologyandphysics).Drugdesignmaybroadlybedividedintotwophases:
➢Basicconceptsabout,anddrugs,receptors,anddrug-receptorinteractions
➢Basicconceptsaboutdrug-receptorinteractionsappliedtohumans.
BASICCONCEPTSOFDRUGDESIGN

15. Quantitativestructure-activityrelationship(QSAR)isaligand-baseddrugdesign
methoddevelopedmorethan50yearsagobyCorwinHansch&Fujitaintheearly
1960s.extendingtheconceptofLinearFreeEnergyRelationships(LFER)todescribe
theefficacyofabiologicallyactivemolecule.Itisamathematicalrelationshipthat
correlates,measurable,andcalculablemolecularpropertiestosomespecific
biologicalactivity.Thebiologicalactivityofamolecularsystemanditsgeometrical
andchemicalcharacteristics(identifyandquantify).Thisapproachquantitatively
relatedthestructureofacompoundtoitsactivityandtheresultingequationswere
namedQuantitativeStructure-ActivityRelationships(QSAR)orQuantitative
Structure-PropertyRelationships(QSPR).Thismethodincreasestheprobabilityof
findingactivecompoundsamongtheEventuallysynthesizedones,thuskeeping
syntheticandscreeningeffortswithinreasonablelimitsinrelationtothesuccessrate.
PhysicochemicalParametersUsedinQSAR
QSARstudiesareconductedingroupsofrelatedcompounds.However,QSARstudies
onstructurallydiversesetsofcompoundsaremorecommon.Inbothcases,awide
rangeofparametersshouldbeconsidered.
QUANTITATIVESTRUCTURE-ACTIVITYRELATIONSHIP

16. PartitionCoefficient(K)
Inordertoreachitssiteofactionadrughastopassthroughafewbiological
membranes.Therefore,organicmedium/aqueoussystempartitioncoefficients(P)are
theparametersconsideredformeasuringtheeaseofmovementofthedrugthrough
thesemembranes.Theaccuracyofthedrugactivitycorrelationwithpartition
coefficientsdependsonthesolventsystemusedasamembranemodel.Forexample,
consistentresultsfordrugsabsorbedintheGITcanbeobtainedusingn-octanol;
consistentcorrelationsfordrugscrossingtheblood-brainbarriercanbeobtainedusing
lesspolarsolvents(likeoliveoil);andmoreconsistentvaluesforbuccalabsorption
(softtissuesinthemouth)canbeobtainedusingmorepolarsolvents(like
chloroform).
PARTITIONCOEFFICIENT
Conc.ofdruginorganicphase
PartitionCoefficient(K)=
Conc.of druginaqueousphase
Organic solvent
Water

17. HAMMET’SELECTRONIC
COOH
+
COO
-
+H
K=6.27*10
-5
HAMMET’SELECTRONIC
TheHammettPlotisatypeofLinearFree-EnergyRelationship(LFER)
analysisdesignedtomodeltheelectroniceffectofsubstituentsonaromatic
systems(intheparaandmetapositionsonly).
TheHammettequationisoneofthemostwidelyappliedrelationsbetween
thestructureandreactivityoforganiccompounds.Thisequationrelatesthe
relativereactivitiesoftheseriesofdi-andpoly-substitutedbenzenederivatives.
Measurestheelectronwithdrawingorelectrondonatingincomparisonto
benzoicacidandhowaffectsitsionization.

18. TAFT’SSTERICPARAMETER
STERICPARAMETER
Stericfeaturesmainlyaffectthedrug-receptorinteractionandreflectthechangeintheonsetordurationofaction.
Thebulkygroupmaylowertheactivitybytheimproperfittingofdrugsintobindingsites.Thesizeofthesubstituent
playsanimportantrolewithrespecttootherparameters.
Taft'sstericfactor(Es):Thisparameterisameasureofsubstituentsizeandisusefulforstudyingintramolecular
stericeffects,particularlyinreactionswherethesubstituentisnearthereactioncenter.Itcanbemeasured
experimentallybymeasuringtheeffect,thatdifferentsubstituentshaveontherateofchemicalreactioncarriedoutin
theparentstructure.Sincethelargersubstituentnexttothereactioncenterbinderthereactionismorethanthe
smallersubstituent.Therefore,thedifferencebetweenthereactionratesoftheparentreactionandthesubstituted
reactionleadstothemeasureofsubstituentsize.Sinceacidhydrolysisofanesterisalmostdeterminedbyasteric
factor,
Esmaybedefinedas:
Es=log(K/K0)A
K=Esterhydrolysisrateconstantforsubstitutedcompound
K0=Esterhydrolysisrateconstantformethylderivative
A=Acidhydrolysis.

19. HANSCHANALYSIS
HanschEquation:
Thebiologicalactivityofmostdrugsisrelatedtoacombination
ofphysicochemicalproperties.Insuchcases,simpleequations
involvingonlyoneparameterarerelevantonlyiftheother
parametersarekeptconstant.Inreality,thisisnoteasytoachieveand
equationswhichrelate,biologicalactivitytomorethanoneparameter
aremorecommon.TheseequationsareknownasHanschequations
andtheyusuallyrelatebiologicalactivitytothemostcommonlyused
physicochemicalproperties(Pand/or,n,andastericfactor).Ifthe
rangeofhydrophobicityvaluesislimitedtoasmallrangethenthe
equationwillbelinearasfollows:
Log=log(1/C)=k1logP+k2ok3E1+k4

20. AdvantagesofQSAR
➢Itprovidesaquantifyingrelationshipbetweenthestructureandactivityontheirphysiochemicalproperty
basis.
➢Itispossibletopredictdesignedcompoundsbeforethechemicalsynthesisofnovelanalogs.
➢Ithelpsinunderstandingtheinteractionsbetweenfunctionalgroupsofdesignedmoleculesandthe
activityofthetargetenzymeorprotein
DisadvantagesofQSAR
➢Itmayprovideincorrectcorrelationsduetobiologicaldataexperimentalerror.
➢Iftherearefewertrainingsetsofmolecules,thedatamaynotreflectthecompletepropertyandthus cannotbe
usedforpredictingactivecompounds.
➢Insome3D-QSARstudy,ligand-bindingreceptororproteinisnotavailable.
➢ItisnotnecessarythattheQSARstudygivessuccessfulresultsoneachapplication.

21. -SIDDHI SHRIGIRIWAR
THANKYOU