1 drug discovery _ design 8 jan 2016

8/18/2019 1 Drug Discovery _ Design 8 Jan 2016

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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; Computeraided drug design: Principles of !A", #D !A", $D !A"; Chemical

development, Patenting, Process development; %o&icology, Pharmacology,

Drug metabolism, Clinical trials, Commerciali'ation: regulatory affairs, pipeline

development, pharmaceutical market places, business opportunities(

Texts:)( *( %homas, Fundamentals of Medicinal Chemistry, +ohn iley - !ons .td(,

#//0(

#( *( Patrick, An Introduction to Medicinal Chemistry, 1&ford 2niversity Press,

#//)(

e!eren"es:

)( *( Patrick, Instant Notes: Medicinal Chemistry, 3iva 4ooks Pvt( .td(, #//#(

#( %( 5ogrady, Medicinal Chemistry: A Biochemical Approach, 1&ford

2niversity Press, #//6(

$( !( Pidgeon, Wiley handbook of Current and mer!in! "ru! #herapies, $ol%

&, iley78nterscience, #//9(60)0 )


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More Reference Books:

1. Biochemistry, sixth edition, Jeremy M. Berg, John L. Tymoczko andLubert tryer! ". #. $reeman and %om&any, 'e(york, )**+.

. -rinci&es of Biochemistry, rd edition, by /oet, /oet and -ratt, John

"iey and ons, )**0.

. 2ntroduction to -rotein tructure, )nd 3dition, by %ar Branden and John

Tooze, Tayor and francis grou&, 1444.

Marks distribution:

1. ) ur&rise 5uizes: 1*6

). Midsem 3xam: *6

. 3ndsem 3xam: *6

. attendance: 1*6

+76 attendance is mandatory for the institute

60)0 #


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MODERN DRUG DISCOVERY

DESIGN ANDDEVELOPMENT

Reference:Patrick

An Introduction to Medicinal Chemistry


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"hat is a drug 8

• 9 chemica com&ound that brings a &ositie change in ife

(hen a&&ied &ro&ery• 9 knife 8 ;;'o

• ugar 8 ;;

• 9 drugs are &oisons at certain concentration

• 9 &oisons are not drug


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?nmet medica need

"hy are ne( drugs needed8

• ne( diseases =92@, 9zheimerAs, obesity>!

• o( efficacy =dementia, cancer>!• side effects =antide&ressants, anti&sychotics>

• cost of thera&y =2ntereukins>

• sustain industria actiity = &harmaceutica industry em&oys

thousands and makes a massie contribution to oerseasearnings, &atent ex&iry>


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Discovery vs. Development

•@rug discoery is the process by which drugsare discovered.

• @iscoery 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 DrugDiscovery &

Design

'e( %hemica 3ntity

Sources: Organic Synthesis,

olecular odification,

Isolation from plants

-recinica tudies

!hemistry, "hysical

"roperties, #iological

"roperties, "reformulation

2'@

Investigational $ew Drug

%pplication

%inica Trias

"hase I, II, III

-recinica tudies

!ontinued&&&..

'@9

$ew Drug %pplication

-ostmarketing

"hase I' !linical Studies

%dverse (eaction (eporting, &&&


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New DrugDiscovery &

Design

'e( %hemica 3ntity -recinica tudies

2'@

%inica Trias-recinica tudies

'@9

-ostmarketing

In average, only one out of 10,000

originally synthesized compounds will be a

commercially available drug.

Discovering and bringing one new drug to

the public typically costs a pharmaceutical or

biotechnology company nearly )*++ million

and taes an average of 10 to 12 years.


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Traditional Drug Discovery and Development:

Expensive and Time-Consuming

• #efore the twentieth century medicines consisted mainly of herbs and

potions. In mid-nineteenth century first serious efforts were made toisolate and purify the active principles of these remedies.

• hese natural products initiated a ma/or scientific effort and chemistsmade thousands of analogues to improve the natural products.

• uch of these wors was carried out on atria;and;error basis.

• he mechanism of drug action was almost unnown.

• (esearchers focused on the lead compound- the active constituentisolated from the natural source.

•

his is e0tremely time-consuming and cost-intensive.


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Modern Drug Discovery:

More Efficient Development troug te Coordination of !rocesses and Data

•%dvances in many branches of science helped the process ofdrug discovery and design.

• he shortcoming of traditional drug discovery1 as well as a moredeterministic approach to combating disease has led to the

concept of 2(ational drug design2 34untz 5**67.

• 8or 2rational2 design, the first necessary step is the identificationof a molecular target critical to a disease process or an infectious pathogen. hen the important prere9uisite of 2drug design2 is the

determination of the molecular structure of target.

• he new approach to drug discovery overcomes the limitationsof traditional research.


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RUG DESIGN AND DEVELOPMENT

Stages

) Identify target disease

) Identify drug target

) Establish testing procedures

) Find a lead compound

) Structure Activity Relationships (SAR)

) Identify a pharmacophore

) Drug design- optimising target interactions

) Drug design - optimising pharmacokinetic properties

) Toxicological and safety tests

0) Chemical development and production

1) Patenting and regulatory affairs

2) Clinical trials


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1. TARGET DISEASE

Priority for the Pharmaceutical Industry

• Can the profits from marketing a new drug outweigh the

cost of developing and testing that drug?

Questions to be addressed

• Is the disease widespread?

(e.g. cardiovascular disease, ulcers, malaria)• Does the disease affect the first world?

(e.g. cardiovascular disease, ulcers)• Are there drugs already on the market?• If so, what are there advantages and disadvantages?

(e.g. side effects)• Can one identify a market advantage for a new therapy?


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. DRUG TARGETS

A) LIPIDS

Cell Membrane [amphotericin B (antifungal agent)]

B) PROTEINS Receptors [Ranitidine] Enzymes [Captopril –

an ACE inhibitor]

Carrier Proteins [Omeprazole – a proton pump inhibitor]

Structural Proteins (tubulin) [Docetaxel – an anticancer agent]

C) NUCLEIC ACIDS DNA [Cisplatin – antitumour agent]

RNA [Chloramphenicol acts on mRNA]

D) CARBOHYDRATES [usually not targeted ]Cell surface carbohydrates Antigens and

recognition molecules


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Target your mouse cursor athis nose ... For 5 seconds

ee hee hee


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a. in vivo Te!t! • Carried out on live animals or humans

• Measure an observed physiological effect

• Tests not carried out on animals/humans

Target molecules (e.g. isolated enzymes or receptors), Cells

(e.g. cloned cells), Tissues (e.g. muscle tissue), Organs, Micro-

organisms (for antibacterial agents)• More suitable for routine testing

". in vitro Te!t!


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Introduction

T$e Lea% C&'(&)n%

• 9 com&ound demonstrating a &ro&erty ikey to bethera&euticay usefu

• The ee of actiity and target seectiity are not crucia• ?sed as the starting &oint for drug design and deeo&ment•

$ound by design =moecuar modeing or 'MR> or byscreening com&ounds =natura or synthetic>

• 'eed to identify a suitabe test in order to find a ead

com&ound• 9ctie -rinci&e ; a com&ound that is isoated from a natura

extract and (hich is &rinci&ay res&onsibe for the extractAs

&harmacoogica actiity. ften used as a ead com&ound.


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. S&)rce! &f Lea% C&'(&)n%!

A) The Natural World

B) The Synthetic World

C) The Virtual World

Plantlife (flowers, trees, bushes)

Micro-organisms (bacteria, fungi)

Animal life (frogs, snakes, scorpions)

Biochemicals (Neurotransmitters, hormones)

Marine chemistry (corals, bacteria, fish etc)

Chemical synthesis (traditional)

Combinatorial synthesis

Computer aided drug design


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Lea% C&'(&)n%! fr&' t$e Nat)ra* +&r*%

POPPY CAPSULE

MORPHINE

PLANT EXTRACTS• Egypt: Opium poppy (morphine)

• India: Reserpine- from snakeroot plant

• England: Digitalis- from foxglove

• Greece: Atropine – from solanaceae plants.

Medical Folklore

• %hina: Rhubarb root C • 9nthra5uinones.


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. S&)rce! &f Lea% C&'(&)n%!

Serendipity and the Prepared Mind

"ord "ar 22 ; Mustard Das ; @estruction of "B%; ?raci

Masterd for treatment of eukemia.

Rubber 2ndustry ; disgust for acoho ; antioxidant;

@isufiram for the treatment of chronic acohoism.

u&honamide =9ntibacteria> side effect C o(ering of bood

gucose C Tobutamide C an antidiabetic. @eeo&ment of a heart drug ; idenafi C a bock buster

drug for erectie dysfunction.


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The Past

Lead Compound

Targets

Targets

Lead compounds

The Future

#. Lea% C&'(&)n%! - Impact of the human genome project


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The design of novel agents based on a knowledge of the target

binding site

.11 De N&,& Dr)- De!i-n

Procedure• Crystallise target protein with bound ligand

(e.g. enzyme + inhibitor or ligand)

• Acquire structure by X-ray crystallography• Identify binding site (region where ligand is bound)• Remove ligand• Identify potential binding regions in the binding site

• Design a lead compound to interact with the binding site• Synthesise the lead compound and test it for activity• Crystallise the lead compound with target protein and identify

the actual binding interactions•

Structure based drug design


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Receptor

. Lea% C&'(&)n%! de novo %e!i-n


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Scaffold

CO2-

HOIONIC

BOND

H-

BON

D

VDW

BOND

ScaffoldScaffold

Scaffold

ScaffoldH3N+

O

CH3


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. De!i-n &f Lea% C&'(&)n%! )!in-MR S(ectr&!c&(/

• 'MR ='ucear Magnetic Resonance> s&ectrosco&y is used to

design a lead compound rater tan to discover one.

• This method starts to find out sma moecues =e&ito&es>.

3&ito&es (i bind to s&ecific but different regions a a &roteinAs

binding site.

• These moecues (i hae no actiity in themsees.

• But if a arger moecue is designed (hich inks these e&ito&estogether, then a ead com&ound may be created (hich binds to

the (hoe of the binding site and may hae actiity.


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H

N

HO

OOH

N

OO

OMe

OMe

MeO

O

O

Me

Design of a lead compound as an immunosuppressant


Lead compound


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I%enti0cati&n &f Lea% C&'(&)n%!

A) Isolation and purification

solvent-solvent extraction

chromatography crystallisation

distillation

B) Structure determinationelemental analysis

molecular weight mass spectrum

infra red

ultra violet nmr (1H, 13C,2D) X-ray crystallography



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". an!c$ E3)ati&n • A QSAR equation relating various physicochemical properties

to the biological activity of a series of compounds

• Usually includes log P, electronic and steric factors

• Start with simple equations and elaborate as more structures

are synthesised

• Typical equation for a wide range of log P is parabolic

Log 1C = -k (logP)2 + k 2 logP + k 3 σ + k 4 E s + k 51

Log1C

-0.034(Σ

)2 -0.33Σ

+ 4.3( F-5) + 1.3 ( R-5) - 1.7(Σ

)2 + 0.73(345- HBD)

- 0.86 (HB-INTRA) - 0.69(NHSO2) + 0.72(4-OCO) - 0.59


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Stage 6 Optimum Structure and binding theory

NH3

X

X

XXH

5

3

NH

NH

C

O

CH

OH

CH2OH

CH CH2OHC

O OH

RHN


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1 drug discovery _ design 8 jan 2016

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