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FINDINGALEAD
DRUGDESIGNANDDEVELOPMENT
Stages
1)Identifytargetdisease
2)Identifydrugtarget
3)Establishtestingprocedures
4)Findaleadcompound
5)StructureActivityRelationships(SAR)
6)Identifyapharmacophore
7)Drugdesignoptimisingtargetinteractions
8)Drugdesignoptimisingpharmacokineticproperties
9)Toxicologicalandsafetytests
10)Chemicaldevelopmentandproduction
11)Patentingandregulatoryaffairs
12)Clinicaltrials
DRUGDESIGNANDDEVELOPMENT
Stages
1)Identifytargetdisease
2)Identifydrugtarget
3)Establishtestingprocedures
4)Findaleadcompound
5)StructureActivityRelationships(SAR)
6)Identifyapharmacophore
7)Drugdesignoptimisingtargetinteractions
8)Drugdesignoptimisingpharmacokineticproperties
9)Toxicologicalandsafetytests
10)Chemicaldevelopmentandproduction
11)Patentingandregulatoryaffairs
12)Clinicaltrials
1.TARGETDISEASE
PriorityforthePharmaceuticalIndustry
Cantheprofitsfrommarketinganewdrugoutweighthecostof
developingandtestingthatdrug?
Questionstobeaddressed
Isthediseasewidespread?
(e.g.cardiovasculardisease,ulcers,malaria)
Doesthediseaseaffectthefirstworld?
(e.g.cardiovasculardisease,ulcers)
Aretheredrugsalreadyonthemarket?
Ifso,whataretheiradvantagesanddisadvantages(e.g.sideeffects)
Canoneidentifyamarketadvantageforanewtherapy?
2.DRUGTARGETS
A)Lipids
Cellmembranelipids
B)Proteins
Receptors
Enzymes
Carrierproteins
Structuralproteins(tubulin)
C)Nucleicacids
DNA
RNA
D)Carbohydrates
Cellsurfacecarbohydrates
Antigensandrecognitionmolecules
2.DRUGTARGETS
Targetselectivity
Betweenspecies
Antibacterial,antifungalandantiviralagents
Identifytargetswhichareuniquetotheinvadingpathogen
Identifytargetswhicharesharedbutwhicharesignificantlydifferentin
structure
Withinthebody
Selectivitybetweendifferentenzymes,receptorsetc.
Selectivitybetweenreceptortypesandsubtypes
Selectivitybetweenisozymes
Organandtissueselectivity
3.TESTINGDRUGS
Tests are required in order to find lead compounds and for
drugoptimisation
Testscanbeinvivoorinvitro
Acombinationoftestsisoftenusedinresearchprogrammes
3.1invivoTests
Carriedoutonliveanimalsorhumans
Measureanobservedphysiologicaleffect
Measure a drugs ability to interact with its target and its
abilitytoreachthattarget
Canidentifypossiblesideeffects
Rationalisation may be difficult due to the number of factors
involved
Transgenicanimalsgeneticallymodifiedanimals
Drugpotencyconcentrationofdrugrequiredtoproduce50%
ofthemaximumpossibleeffect
Therapeutic ratio/index
comparesthedoselevelofadrugrequiredtoproducea
desiredeffectin50%ofthetestsample(ED50)versus
thedoselevelthatislethalto50%ofthesample(LD50)
3.2invitroTests
Testsnotcarriedoutonanimals/humans
Targetmolecules(e.g.isolatedenzymesorreceptors)
Cells(e.g.clonedcells)
Tissues(e.g.muscletissue)
Organs
Microorganisms(forantibacterialagents)
Moresuitableforroutinetesting
Usedinhighthroughputscreening
Measuretheinteractionofadrugwiththetargetbutnotthe
abilityofthedrugtoreachthetarget
Resultsareeasiertorationaliselessfactorsinvolved
Doesnotdemonstrateaphysiologicalorclinicaleffect
Doesnotidentifypossiblesideeffects
Doesnotidentifyeffectiveprodrugs
3.2.1EnzymeInhibitionTests
Identifycompetitiveornoncompetitiveinhibition
StrengthofinhibitionmeasuredasIC50
IC50=concentrationofinhibitorrequiredtoreduceenzyme
activityby50%
3.2.2TestingwithReceptors
Noteasytoisolatemembraneboundreceptors
Carriedoutonwholecells,tissuecultures,orisolatedorgans
Affinitystrengthwithwhichcompoundsbindtoareceptor
Efficacymeasureofmaximumbiochemicaleffectresultingfrom
bindingofacompoundtoareceptor.
Potencyconcentrationofanagonistrequiredtoproduce50%
ofthemaximumpossibleeffect.
4TheLeadCompound
A compound demonstrating a property likely to be
therapeuticallyuseful
Thelevelofactivityandtargetselectivityarenotcrucial
Usedasthestartingpointfordrugdesignanddevelopment
Found by design (molecular modelling or NMR) or by
screeningcompounds(naturalorsynthetic)
Needtoidentifyasuitabletestinordertofindaleadcompound
Active Principle a compound that is isolated from a natural
extract and which is principally responsible for the extracts
pharmacologicalactivity.Oftenusedasaleadcompound.
4.1SourcesofLeadCompounds
A)TheNaturalWorld
Plantlife(flowers,trees,bushes)
Microorganisms(bacteria,fungi)
Animallife(frogs,snakes,scorpions)
Biochemicals(Neurotransmitters,hormones)
Marinechemistry(corals,bacteria,fishetc)
B)TheSyntheticWorld
Chemicalsynthesis(traditional)
Combinatorialsynthesis
C)TheVirtualWorld
Computeraideddrugdesign
4.2IdentificationofLeadCompounds
A)Isolationandpurification
solventsolvent extraction
chromatography
crystallisation
distillation
B)Structuredetermination
elemental analysis
molecular weight
mass spectrometry
infra red spectroscopy
ultra violet spectroscopy
nmr (1H, 13C, 2D)spectroscopy
Xraycrystallography
4.3LeadCompoundsfromtheNaturalWorld
PLANTEXTRACTS
4.3LeadCompoundsfromtheNaturalWorld
PLANTEXTRACTS
MORPHINE
POPPYCAPSULE
4.3LeadCompoundsfromtheNaturalWorld
PLANTEXTRACTS
OPIUM Morphine
CINCHONABARKQuinine
YEWTREE Taxol
4.3LeadCompoundsfromtheNaturalWorld
PLANTEXTRACTS
WILLOWTREESALICYLICACID
O
OH
OH
Acetic
anhydride
OH
CH3
O
O
Aspirin
COCABUSHCOCAINE
Me
N
CO2Me
H
C
O
Procaine
O
H
CH3
CH3
C
O
NH2
4.3LeadCompoundsfromtheNaturalWorld
PLANTSANDANCIENTRECORDS
4.3LeadCompoundsfromtheNaturalWorld
PLANTSANDANCIENTRECORDS
CH3
H
O
H3 C
O
O
H
H
O
H
O
ARTEMISININ
CH3
4.3LeadCompoundsfromtheNaturalWorld
PLANTSANDANCIENTRECORDS
CH3
H
O
H3 C
O
O
H
H
O
H
O
ARTEMISININ
CH3
4.3LeadCompoundsfromtheNaturalWorld
PLANTSANDANCIENTRECORDS
CH3
H
O
H3 C
O
O
H
H
O
H
O
ARTEMISININ
CH3
Fe
4.3LeadCompoundsfromtheNaturalWorld
PLANTSANDANCIENTRECORDS
THEBEATONSOFPENNYCROSS
THEBEATONSOFPENNYCROSS
CUREforEPILEPSY
Addaliberalsprinkling
Flavourwithessence
Heatacauldronofwater
Simmerfor20minutes
Produceonepedigreedog
ofjuicyspiders
ofdogturd
untilwarmtothetouch
thenenjoy
4.3LeadCompoundsfromtheNaturalWorld
HERBALREMEDIESOFOLDE
Majoritymayhaveworkedthroughaplaceboeffect
4.3LeadCompoundsfromtheNaturalWorld
RAINFORESTS
4.3LeadCompoundsfromtheNaturalWorld
CORALANDMARINECHEMISTRY
CH3
OMe
CURACIN
CH3
H
4.3LeadCompoundsfromtheNaturalWorld
MICROORGANISMS
4.3LeadCompoundsfromtheNaturalWorld
MICROORGANISMS
R
PENICILLIN
CEPHALOSPORINS
TETRACYCLINES
STREPTOMYCIN
CHLORAMPHENICOL
CHLORAMPHENICOL
H H H
N
NH
O HN
S
CH
3
H
H HN C NH2
H
R OC NC H
NH
H2N
N S CH
H 3
O
H
OH
OH O H
O OAc
O
N OH
CO
2H
HO
OH
O H
OH
NH2
COH
2H
O
H
O
OH
CHO
H
Me
H
Me
ClHO
NMe2
OH
HO H
H
O
O
HO 2N O
CH2OH
CH2OH
H MeHN
HN H
H
H
C
OH H
CHCl2
O
4.3LeadCompoundsfromtheNaturalWorld
VENOMSANDTOXINS
C OH
O
C
Teprotide
O
H2N CH C
N CH C
H
CH2
CH2
CH2
C O
OH
HN
N CH C
H
CH2
CH2
CH2
N CH C
H
CH2
H
N CH C
CH CH3
CH2
CH2
C O
CH3
NH2
O
C OH
NH
C NH
NH2
HS
N
CH3
Captopril
(antihypertensive)
4.3LeadCompoundsfromtheNaturalWorld
VENOMSANDTOXINS
4.3LeadCompoundsfromtheNaturalWorld
MeO
VENOMSANDTOXINS
HO
O
H3 C
H3 C
H
N
CH 3
CH 3
O
OH
OMe
Tubocurarine
(fromcurare)
4.3LeadCompoundsfromtheNaturalWorld
MeO
VENOMSANDTOXINS
HO
O
H3 C
H3 C
CH 3
CH 3
OH
OMe
Tubocurarine
(fromcurare)
MeO
MeO
CH 3
OMe
OMe
(CH 2)5
OMe
H
MeO
OMe
Atracurium
(Neuromuscularblocker)
OMe
4.3LeadCompoundsfromtheNaturalWorld
ENDOGENOUSCOMPOUNDS
NATURALLIGANDSFORRECEPTORS
OH
HO
OH
H
N
Me
HO
H
N
Agonist
HO
HO
ADRENALINE
SALBUTAMOL
NH2
HO
NMe2
MeHN
N
H
5-HYDROXYTRYPTAMINE
Agonist
N
H
SUMATRIPTAN
4.3LeadCompoundsfromtheNaturalWorld
ENDOGENOUSCOMPOUNDS
NATURALLIGANDSFORRECEPTORS
OH
H
N
HO
O
OH
Me
Antagonist
N
H
HO
ADRENALINE
NH2
HN
N
HISTAMINE
PROPRANOLOL
Me
HN
S
N
CIMETIDINE
H
N
NHMe
CN
Antagonist
4.3LeadCompoundsfromtheNaturalWorld
ENDOGENOUSCOMPOUNDS
NATURALSUBSTRATESFORENZYMES
Enkephalins
Enkephalinaseinhibitors
Peptides
Proteaseinhibitors
H CO2H
H2N
H H
N
N
H
LPheLPro
H
N
H H
CONH2
SAQUINAVIR
H
N
OH
H
N
H
H
4.4LeadCompoundsfromtheSyntheticWorld
SYNTHETICCOMPOUNDS
4.4LeadCompoundsfromtheSyntheticWorld
O
H2N
N
NH2
S
O
NH2
PRONTOSIL
4.4LeadCompoundsfromtheSyntheticWorld
O
H2N
S
O
SULFANILAMIDE
NH2
4.4LeadCompoundsfromtheSyntheticWorld
TNT
ONO2
ONO2
ONO2
4.4LeadCompoundsfromtheSyntheticWorld
RUBBERINDUSTRY
CH3
S
H3C
H3C
C
S
ANTABUSE
CH3
4.4LeadCompoundsfromtheSyntheticWorld
ORGANICSYNTHESIS
4.4LeadCompoundsfromtheSyntheticWorld
COMBINATORIALSYNTHESIS
AUTOMATEDSYNTHETICMACHINES
4.4LeadCompoundsfromtheSyntheticWorld
COMBINATORIALSYNTHESISPEPTIDESYNTHESIS
AMINOACID
RESIN
BEAD
AMINOACIDS
PEPTIDE
4.4LeadCompoundsfromtheSyntheticWorld
COMBINATORIALSYNTHESISHETEROCYCLICSYNTHESIS
RESIN
BEAD
N
N
Y
CHR1R2
4.4LeadCompoundsfromtheSyntheticWorld
COMBINATORIALSYNTHESISHETEROCYCLICSYNTHESIS
N
N
R2
R3
H
RESIN
BEAD
4.4LeadCompoundsfromtheSyntheticWorld
COMBINATORIALSYNTHESISHETEROCYCLICSYNTHESIS
N
N
R2
R3
R4
R5
EtO
O
RESIN
BEAD
4.4LeadCompoundsfromtheSyntheticWorld
COMBINATORIALSYNTHESISHETEROCYCLICSYNTHESIS
N
N
R2
R3
R4
R5
HN
O
RESIN
BEAD
4.4LeadCompoundsfromtheSyntheticWorld
COMBINATORIALSYNTHESISHETEROCYCLICSYNTHESIS
N
N
RESIN
BEAD
Y
R2
R3
R4
R5
HN
O
4.5LeadCompounds
Impactofthehumangenomeproject
ThePast
LeadCompound
Targets
ThePresentandFuture
Targets
Leadcompounds
4.5LeadCompounds
Impactofthehumangenomeproject
4.5LeadCompounds
Impactofthehumangenomeproject
4.5LeadCompounds
Impactofthehumangenomeproject
4.5LeadCompounds
Impactofthehumangenomeproject
4.5LeadCompounds
Impactofthehumangenomeproject
4.6LeadCompoundsdenovodesign
4.6LeadCompoundsdenovodesign
XRAYCRYSTALLOGRAPHY
4.6LeadCompoundsdenovodesign
PROTEINSTRUCTURE
1.Denovodesign
Thedesignofnovelleadcompoundsbasedonthestructureofthe
bindingsite
Procedure
Crystalliseprotein+ligand
Downloadformolecularmodellingstudies
Identifythebindingsite
Identifybindinginteractions
Identifyotherbindingregionsinthebindingsite
Removeligandinsilico
Designligandstofitandbindtothebindingsiteinsilico
Calculatestrengthofbinding
Synthesiseandtestpromisingstructures
Optimisebystructurebaseddrugdesign
LeadCompoundsdenovodesign
Notes
Automatedprogram
Fragmentbasedprocess
Generatessyntheticallyfeasiblystructures
Syntheticrulesincorporatedintostructurebuildingprocess
Fragmentsmustbecommerciallyavailable
Fragmentsonlylinkedifsyntheticallyfeasible
Programprovidespossiblesyntheticroute
4.6LeadCompoundsdenovodesign
Receptor
CH3
IONIC
BOND
+
H3N
CO2
Scaffold
Scaffold
Scaffold
Scaffold
Scaffold
VDW
BOND
O
HO
HBOND
4.6LeadCompoundsdenovodesign
Thymidylatekinaseinhibitors
NH
HN
N
S
Optimisation
O
N
H2 N
N
S
O
ANTICANCERAGENT
Leadcompound
4.7DesignofLeadCompoundsusingNMRSpectroscopy
NMRSPECTROSCOPY
4.7DesignofLeadCompoundsusingNMRSpectroscopy
BindingSite
Protein
4.7DesignofLeadCompoundsusingNMRSpectroscopy
Protein
NOOBSERVABLEBIOLOGICALEFFECT
4.7DesignofLeadCompoundsusingNMRSpectroscopy
CH3
CH CH
CH2
CH2
C
CH
CNMR
13
CH3
4.7DesignofLeadCompoundsusingNMRSpectroscopy
CH CH
CH2
CH2
C
CH
CNMR
13
CH3
CH3
4.7DesignofLeadCompoundsusingNMRSpectroscopy
Protein
Optimise
epitope
4.7DesignofLeadCompoundsusingNMRSpectroscopy
Protein
Optimise
epitope
Optimise
epitope
4.7DesignofLeadCompoundsusingNMRSpectroscopy
Link
Protein
Optimise
epitope
Optimise
epitope
4.7DesignofLeadCompoundsusingNMRSpectroscopy
LEADCOMPOUND
4.7DesignofLeadCompoundsusingNMRSpectroscopy
Designofaleadcompoundasanimmunosuppressant
OH
O
OMe
N
O
MeO
HO
N
H
EpitopeB
OMe
OMe
EpitopeA
4.7DesignofLeadCompoundsusingNMRSpectroscopy
Designofaleadcompoundasanimmunosuppressant
OH
O
OMe
N
O
MeO
HO
OMe
OMe
Leadcompound
N
H
Desirablepropertiesofdrug
LipinskisRuleofFive
Orally active drugs generally show a balance of hydrophilic /
hydrophobicpropertiesandobeythefollowingrules:
MW<500
Nomorethan5HBDgroups
Nomorethan10HBAgroups
logP<+5
Notfoolproofseveralexceptions
Desirablepropertiesoflead
MWshouldbebetween100350amu
clogPvalue13(mesureofhydrophobiccharacter)
generallythewtincreaseby80amuandclogPvaluechangeby
1whilegoingfromleadtodrugso
MW<300
Nomorethan3HBDgroups
Nomorethan3HBAgroups
clogP<+3
Nomorethan3rotatablebonds
Apolarsurfaceareaof60sqA0
Notfoolproofseveralexceptions