Professional Documents
Culture Documents
(3-0-0-6)
What is a drug ?
Preclinical Studies
Chemistry, Physical
Properties, Biological
Properties, Preformulation
IND
Investigational New Drug
Application
Clinical Trials
Preclinical Studies
Continued..
NDA
New Drug
Discovery &
Design
Preclinical Studies
IND
Preclinical Studies
Clinical Trials
NDA
Postmarketing
New Drug
Discovery &
Design
works
was
carried
out
on
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. TARGET DISEASE
PriorityforthePharmaceuticalIndustry
Cantheprofitsfrommarketinganewdrugoutweighthe
costofdevelopingandtestingthatdrug?
Questionstobeaddressed
Isthediseasewidespread?
(e.g.cardiovasculardisease,ulcers,malaria)
Doesthediseaseaffectthefirstworld?
(e.g.cardiovasculardisease,ulcers)
Aretheredrugsalreadyonthemarket?
Ifso,whatarethereadvantagesanddisadvantages?
(e.g.sideeffects)
Canoneidentifyamarketadvantageforanewtherapy?
1
2. DRUG TARGETS
A)LIPIDS
CellMembrane[amphotericinB(antifungalagent)]
B)PROTEINS
Receptors[Ranitidine]
Enzymes[Captopril
anACEinhibitor]
CarrierProteins[Omeprazoleaprotonpumpinhibitor]
StructuralProteins(tubulin)[Docetaxelananticancer agent]
C)NUCLEICACIDS
DNA[Cisplatinantitumouragent]
RNA[ChloramphenicolactsonmRNA]
D)CARBOHYDRATES[usuallynottargeted]
Cellsurfacecarbohydrates
recognitionmolecules
Antigensand
Carriedoutonliveanimalsorhumans
Measureanobservedphysiologicaleffect
Testsnotcarriedoutonanimals/humans
Targetmolecules(e.g.isolatedenzymesorreceptors),Cells
(e.g.clonedcells),Tissues(e.g.muscletissue),Organs,Micro
organisms(forantibacterialagents)
Moresuitableforroutinetesting
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
1
Egypt:Opiumpoppy(morphine)
India:Reserpinefromsnakerootplant
PLANTEXTRACTS
England:Digitalisfromfoxglove
Greece:Atropinefromsolanaceaeplants.
MORPHINE
POPPYCAPSULE
Rubber Industry - disgust for alcohol - antioxidantDisulfiram for the treatment of chronic alcoholism.
4. Lead Compounds
Impactofthehumangenomeproject
ThePast
<>
LeadCompound
Targets
TheFuture
Targets
Leadcompounds
Receptor
+
H3N
IONIC
BOND
CO2
CH3
O
Scaffold
Scaffold
Scaffold
HO
Scaffold
Scaffold
H
BON
D
VDW
BOND
1
Protein
Link
Protein
Optimise
epitope
Optimise
epitope
OH
O
OMe
N
O
MeO
HO
N
H
OMe
OMe
Leadcompound
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
(SAR)
AQSARequationrelatingvariousphysicochemicalproperties
tothebiologicalactivityofaseriesofcompounds
UsuallyincludeslogP,electronicandstericfactors
Startwithsimpleequationsandelaborateasmorestructures
aresynthesised
TypicalequationforawiderangeoflogPisparabolic
2 + k logP + k + k Es + k
Log 1C k(logP)
1
2
3
4
5
1
Log C 0.034( ) 2 0.33 + 4.3(F5) + 1.3(R5) 1.7( )2 + 0.73(345 HBD)
0.86(HBINTRA)0.69(NHSO2)+ 0.72(4OCO) 0.59
Stage6OptimumStructureandbindingtheory
XH
NH
RHN
OH
CH
CH2 OH
CH
CH2 OH
OH
3
5
NH
NH3
6. Pharmacophore
OH
HO
NHCH3
HO
Build3D
model
Activeconformation
Definepharmacophore
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