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CH 428

Drug Design and Development

(3-0-0-6)

Drug targets; Pharmacokinetics: ADME, administration and dosing; Drug


testing: in vivo, in vitro; Drug discovery: natural lead, synthetic lead,
combinatorial synthesis; Pharmacokinetics based drug design; Computer
aided drug design: Principles of QSAR, 2D QSAR, 3D QSAR; Chemical
development, Patenting, Process development; Toxicology, Pharmacology,
Drug metabolism, Clinical trials, Commercialization: regulatory affairs, pipeline
development, pharmaceutical market places, business opportunities.
Texts:
1. G. Thomas, Fundamentals of Medicinal Chemistry, John Wiley & Sons Ltd.,
2006.
2. G. Patrick, An Introduction to Medicinal Chemistry, Oxford University Press,
2001.
References:
1. G. Patrick, Instant Notes: Medicinal Chemistry, Viva Books Pvt. Ltd., 2002.
2. T. Nogrady, Medicinal Chemistry: A Biochemical Approach, Oxford
University Press, 2004.
3. S. Pidgeon, Wiley handbook of Current and Emerging Drug Therapies, Vol.
4, Wiley-Interscience, 2007.
1
4/6/16

More Reference Books:


1. Biochemistry, sixth edition, Jeremy M. Berg, John L. Tymoczko and
Lubert Stryer; W. H. Freeman and Company, Newyork, 2007.
3. Principles of Biochemistry, 3rd edition, by Voet, Voet and Pratt, John
Wiley and Sons, 2008.
4. Introduction to Protein Structure, 2nd Edition, by Carl Branden and John
Tooze, Taylor and francis group, 1999.
Marks distribution:
1. 2 Surprise quizes: 10%
2. Midsem Exam: 40%
3. Endsem Exam: 40%
4. attendance: 10%
75% attendance is mandatory for the institute
4/6/16

MODERN DRUG DISCOVERY


DESIGN AND
DEVELOPMENT
Reference:
Patrick
An Introduction to Medicinal Chemistry

What is a drug ?

A chemical compound that brings a positive change in life


when applied properly
A knife ?
--No
Sugar ?
--Yes (sometimes)
All drugs are poisons at certain concentration
All poisons are not drug

Why are new drugs needed?

Unmet medical need

new diseases (AIDS, Alzheimers, obesity);


low efficacy (dementia, cancer);
side effects (antidepressants, antipsychotics)
cost of therapy (Interleukins)
sustain industrial activity ( pharmaceutical industry employs
thousands and makes a massive contribution to overseas
earnings, patent expiry)

Discovery vs. Development


Drug discovery is the process by which drugs
are discovered.
Discovery includes:
concept, mechanism,
assay, screening, hit identification, lead
demonstration, lead optimization
Discovery also includes in vivo proof of concept
in animals.
Development begins when the decision is made
to put a molecule into phase I clinical trials.
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New Chemical Entity

Preclinical Studies

Sources: Organic Synthesis,


Molecular Modification,
Isolation from plants

Chemistry, Physical
Properties, Biological
Properties, Preformulation
IND
Investigational New Drug
Application

Clinical Trials

Preclinical Studies

Phase I, II, III

Continued..
NDA

New Drug
Discovery &
Design

New Drug Application


Postmarketing
Phase IV Clinical Studies
Adverse Reaction Reporting,

New Chemical Entity

Preclinical Studies
IND
Preclinical Studies

Clinical Trials
NDA
Postmarketing

In average, only one out of 10,000


originally synthesized compounds will be a
commercially available drug.

New Drug
Discovery &
Design

Discovering and bringing one new drug to


the public typically costs a pharmaceutical or
biotechnology company nearly $900 million
and takes an average of 10 to 12 years.

Traditional Drug Discovery and Development:


Expensive and Time-Consuming
Before the twentieth century medicines consisted mainly of herbs and
potions. In mid-nineteenth century first serious efforts were made to
isolate and purify the active principles of these remedies.
These natural products initiated a major scientific effort and chemists
made thousands of analogues to improve the natural products.
Much
of
these
trial-and-error basis.

works

was

carried

out

on

The mechanism of drug action was almost unknown.


Researchers focused on the lead compound- the active constituent
isolated from the natural source.
This is extremely time-consuming and cost-intensive.

Modern Drug Discovery:


More Efficient Development through the Coordination of Processes and Data

Advances in many branches of science helped the process of


drug discovery and design.
The shortcoming of traditional drug discovery; as well as a more
deterministic approach to combating disease has led to the
concept of "Rational drug design" (Kuntz 1992).
For "rational" design, the first necessary step is the identification
of a molecular target critical to a disease process or an infectious
pathogen. Then the important prerequisite of "drug design" is the
determination of the molecular structure of target.
The new approach to drug discovery overcomes the limitations
of traditional research.
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DRUG DESIGN AND DEVELOPMENT


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. TARGET DISEASE
PriorityforthePharmaceuticalIndustry

Cantheprofitsfrommarketinganewdrugoutweighthe
costofdevelopingandtestingthatdrug?

Questionstobeaddressed

Isthediseasewidespread?
(e.g.cardiovasculardisease,ulcers,malaria)
Doesthediseaseaffectthefirstworld?
(e.g.cardiovasculardisease,ulcers)
Aretheredrugsalreadyonthemarket?
Ifso,whatarethereadvantagesanddisadvantages?
(e.g.sideeffects)
Canoneidentifyamarketadvantageforanewtherapy?
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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

Target your mouse cursor at


his nose ... For 5 seconds

Hee hee hee

3a. in vivo Tests

Carriedoutonliveanimalsorhumans
Measureanobservedphysiologicaleffect

3b. in vitro Tests

Testsnotcarriedoutonanimals/humans
Targetmolecules(e.g.isolatedenzymesorreceptors),Cells
(e.g.clonedcells),Tissues(e.g.muscletissue),Organs,Micro
organisms(forantibacterialagents)

Moresuitableforroutinetesting

4 The Lead Compound


Introduction

A compound demonstrating a property likely to be


therapeutically useful
The level of activity and target selectivity are not crucial
Used as the starting point for drug design and development
Found by design (molecular modelling or NMR) or by
screening compounds (natural or synthetic)
Need to identify a suitable test in order to find a lead
compound
Active Principle - a compound that is isolated from a natural
extract and which is principally responsible for the extracts
pharmacological activity. Often used as a lead compound.

4. Sources of Lead Compounds

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

Lead Compounds from the Natural World


MedicalFolklore
China: Rhubarb root Anthraquinones.

Egypt:Opiumpoppy(morphine)
India:Reserpinefromsnakerootplant

PLANTEXTRACTS

England:Digitalisfromfoxglove
Greece:Atropinefromsolanaceaeplants.
MORPHINE

POPPYCAPSULE

4. Sources of Lead Compounds


SerendipityandthePreparedMind

World War II - Mustard Gas - Destruction of WBC- Uracil


Masterd for treatment of leukemia.

Rubber Industry - disgust for alcohol - antioxidantDisulfiram for the treatment of chronic alcoholism.

Sulphonamide (Antibacterial) side effect lowering of blood


glucose Tolbutamide an antidiabetic.

Development of a heart drug - Sildenafil a block buster


drug for erectile dysfunction.
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4. Lead Compounds
Impactofthehumangenomeproject
ThePast
<>
LeadCompound

Targets

TheFuture
Targets

Leadcompounds

.11 De Novo Drug Design


The design of novel agents based on a knowledge of the target
bindingsite
Procedure
Crystallisetargetproteinwithboundligand
(e.g.enzyme+inhibitororligand)
AcquirestructurebyXraycrystallography
Identifybindingsite(regionwhereligandisbound)
Removeligand
Identifypotentialbindingregionsinthebindingsite
Designaleadcompoundtointeractwiththebindingsite
Synthesisetheleadcompoundandtestitforactivity
Crystallisetheleadcompoundwithtargetproteinandidentify
theactualbindinginteractions
Structurebaseddrugdesign
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. Lead Compounds - de novo design

Receptor

+
H3N
IONIC
BOND

CO2

CH3
O
Scaffold
Scaffold
Scaffold
HO
Scaffold
Scaffold

H
BON
D

VDW
BOND
1

. Design of Lead Compounds using


NMR Spectroscopy
NMR (Nuclear Magnetic Resonance) spectroscopy is used to
design a lead compound rather than to discover one.
This method starts to find out small molecules (epitopes).
Epitopes will bind to specific but different regions a a proteins
binding site.
These molecules will have no activity in themselves.
But if a larger molecule is designed which links these epitopes
together, then a lead compound may be created which binds to
the whole of the binding site and may have activity.
1

. Design of Lead Compounds using


NMR Spectroscopy
BindingSite

Protein

. Design of Lead Compounds using


NMR Spectroscopy

Link

Protein
Optimise
epitope

Optimise
epitope

. Design of Lead Compounds using


NMR Spectroscopy
Designofaleadcompoundasanimmunosuppressant

OH

O
OMe
N
O

MeO

HO

N
H

OMe
OMe

Leadcompound

. Identification of Lead Compounds


A)Isolationandpurification
solventsolvent
extraction
chromatography
crystallisation
distillation
B)Structuredetermination
elemental
analysis
molecularweight
massspectrum
infra
red
ultra violet
nmr (1H, 13C,
2
D)
Xraycrystallography

DRUG DESIGN AND DEVELOPMENT


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

5a) Structure Activity Relationships

(SAR)

5b. Hansch Equation

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

DRUG DESIGN AND DEVELOPMENT


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

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