DRUGDISCOVERY:

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