Drug Discovery Design and Development

8/20/2019 Drug Discovery Design and Development

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DRUG DISCOVERY: FINDING A LEAD

PH CH 129 AY 2010-2011



OBJECTIVESAt the end the student should be able

to:

1. Know the diferent considerations innding a lead compound;

2. Identi y the steps carried out during

the course o drug disco ery! and;". Appreciate the steps and

considerations made in the process

o nding a lead compound.



OUTLINEI. #he $rug $isco ery %rocessII. $rug &creening 'ethodsIII.Isolation and %uri cationI(.&tructure $etermination



THE DRUG DISCOVERY

PROCESS

Compl !T"m

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THE DRUG DISCOVERY PROCESS

%rogram&election

#argetIdenti cati

on and(alidation

)eadIdenti catio

n

)ead*ptimi+ation

%reclinical and

,linical&tudies



THE DRUG DISCOVERY PROCESSP(o'(,

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• ,lear strategy is needed:• -ew agents must ha e statistically pro en

clear ad antages o er e isting therapy• ,onsiderations:

• the medical need• a ailability o current therapy• competitor acti ity•

commercial opportunity




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AIN APPROACHES FOR TARGETIDENTIFICATION• 'olecular %ro ling

• /enomics• %roteomics

• 0ioin ormatics• orward and e erse /enetics




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AINAPPROACHESFOR TARGETVALIDATION• /ene 3noc3out




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AINAPPROACHESFOR TARGETVALIDATION• -A inter erence

4 -Ai5




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6its$isco ery

• eproducible acti ity in rele ant bioassay• ,on rmed structure and high purity• &peci c or target under study• ,on rmed potential or no elty• ,hemically tractable

6it

(alidation

• acti e in vivo• must not display human ether7a7go7go7related

to icity• Analogs must display clear &A• 'ust not contain chemically reacti e unctions• 'ust pro ide patent opportunities

)ead,ompound

• $isplays &A• A$'8 and to icity studies,linical

$rug,andidat




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LEAD CO POUND• 9a compound rom a series o related

compounds that has some o a desiredbiological acti ity

• 9can be characterised! and modi ed toproduce another molecule with a betterpro le o wanted properties to unwanted sideefects

• a rst oothold on the drug disco ery ladder




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• 9me7too compounds• 'ore potent! sa er! better ormulationAnalogue $esign

• &creening new molecules• 8 tensi e s. random screening

&ystematic

&creening• 6umans! animals! plants! microbes

8 ploitation o0iological

In ormation• 0ased on e tensi e 3nowledge o molecular

targets

%lanned esearch

and ationalApproaches

STRATEGIES




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• 'olecules are chemically modi ed andsubse uently characteri+ed in order to obtaincompounds with suitable properties to becomea drug.

•)eads are characteri+ed with respect to:• pharmacodynamic properties in vivo and in

vitro• physiochemical properties• pharmaco3inetic properties




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• o ten the tightest bottlenec3 in drug disco ery

• ,ompounds that do not ul l the re uirementsor a success ul drug de elopment candidate

ha e to be optimi+ed through the synthesis obetter suited deri ati es




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• %reclinical studies in ol e in vitro studies andtrials on animal populations




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#he -I6 organi+es clinical trials into < diferent types:15 #reatment trials: test e perimental treatments or a

new combination o drugs.25 %re ention trials: loo3 or ways to pre ent a disease

or pre ent it rom returning."5 $iagnostic trials: nd better tests or procedures or

diagnosing a disease.=5 &creening trials: test methods o detecting diseases.

<5 >uality o )i e trials: e plore ways to impro e com ortand uality o li e or indi iduals with a chronic illness.



DRUG SCREENINGETHODS



SCREENING OF NATURALPRODUCTS

•?@ o the worldBs population uses drugs e clusi ely rom naturalsources.

• "< o drugs contain CprinciplesB 43ey structure elements5 onatural origin.

• )ess than < o the <@@!@@@ higher plant species ha e undergone

biological pharmacological screening.• 8ach plant has potentially 1@!@@@ diferent constituents.

8 tractmi ture

s

0iological

#est

%uri y

eDect

)8A$,*'%*E-$El&#".,

% (&# &(



E A PLES OF NATURAL PRODUCTS

,8%6A)*&%* I- ,'ould 7 antibiotic

#AF*) Gew tree 7 antitumor

$I&,*$8 '*)I$8'arine sponge 7 antitumorH immunosuppressant

#8% *#I$80ra+ilian iper enom 7 A,8

inhibitor



PROBLE S 3ITH NATURALPRODUCT SCREENING

– Isolation o an acti e component present in a erysmall amount can be

– problematic gi en a large amount o bac3ground9rubbish .

– #he mi tures are o ten ery comple and containmany large macromolecules. #hese can o ten 9hide

biological acti ity. – ,ompound isolation and structure determination

di cult. – &tructures o ten comple ! there ore di cult to

synthesise and identi y the pharmacophore.



SYNTHETIC

CO POUNDLIBRARY • a collection o compounds whose ariety 4di ersity5maybe: – small and ery limited 4e.g. departmental library5!

– big but relati ely limited 4e.g. Eni ersity academiclibrary5!

– big and di erse 4e.g. city library5.• those rom past proDects are 3ept and may be screened

or the biological acti ity you are loo3ing or in a newproDect

• -ew compounds may also be made 9in7house butnowadays specialist chemical companies are o tencontracted to simply ma3e -,8s 4new chemical entities5

or big pharmaceutical companies.



SYNTHETIC

CO POUNDLIBRARY • D"%,.*,$ ,' : o ten o limited

structural di ersity• #wenty or so years ago a bottlenec3

in the modern drug disco ery process

was identi ed problem:How can we access newcompounds as quickly as

possible?



IN VITRO TESTS• $o not in ol e li e animals• Isolated tissues! cells or en+ymes• A.*,$ ,' %:

– ,heaper – 'ore con enient – )ess contro ersial – ,an be automated

• D"%,.*,$ ,' %: – 8fect on undesired target cannot be

determined



IN VITRO TESTSB"o#4 m"#,l-B,% . C ll-5,% .

eagents %artially puri ed orpuri ed macromolecules

,ells and cell culturemedium

Ad antage

s

• continual cell culture is

not re uired• cell permeabilitybarriers are not present

• determination o themechanism o action isgenerallyuncomplicated

• se eral interesting

molecular targets maybe contained in oneassay

• unctional assays can bede eloped

• reagents do not need tobe puri ed

$isad antages

• assay conditions do notreJect the physiologicalen ironment present incells

• do not permit

• determination omechanism o actionmay be complicated

• potential or a highincidence o alse



IN VITRO TESTS• 8 amples: – 8n+yme inhibition

studies – ,ytoto icityassays

–eceptorAgonistsHAntagonis

t #esting – adioligand

studies



IN VIVO TESTS• * ten in ol e inductiono the clinical conditionin the animal to produce

obser able symptoms• Animal is then treated to

see whether the drugeliminates the symptoms

• Ese o transgenicanimals



IN VIVO TESTS• Ad antages: – %harmaco3inetic properties o

a drug can be determined –

&ide efects can bedetermined• $isad antages:

– &low – ,auses animal sufering – esults can sometimes be

misleading – ,ertain tests may turn out to

be in alid



TEST VALIDITY • (alidity o some test procedures

are easy and clear cut• En ortunately some tests are not

clear cut



HIGH-THROUGHPUT

SCREENING• In ol es automated testing o largenumber o compounds ersus a largenumber o targets

• obotics and miniaturi+ation o in vitro tests on genetically modi ed cells

• #ypically: thousand o compounds atonce in "@7<@ biochemical tests

• &hould produce an easily measurableefect! which can be detected andmeasured automatically



SCREENING BY N R• $etection o binding o a compound

to its protein target• R l,!, "o$ "m : time ta3en by

diferent nuclei to gi e of energy asthey go bac3 to their ground state

• Sm,ll mol #&l : long rela ationtime – Only ones detected

• L,(' mol #&l : short rela ationtime



SCREENING BY N R.(&'

p(o "$

N R %p # (o%#op)

N R %p # (o%#op)

N RD # .

N RD # .

Y % No

.(&' p(o "$ .(&' p(o "$



SCREENING BY N R• A.*,$ ,' %: – &creening as much as 1@@@ small7molecular

weight compounds a day with one machine –

,an detect wea3 binding! which would bemissed by con entional screening methods – ,an identi y the binding o small molecules

to diferent regions o the binding site

– ,omplementary to 6#&! ensures the positi eresult in 6#&



SCREENING BY N R• A.*,$ ,' %: – Identi cation o wea3ly binding

molecules allows the possibility o usingthem as building bloc3s or theconstruction o larger molecules thatbind more strongly

– &creening can be done on a new proteinwithout needing to 3now its unction

• L"m" , "o$: –

At least the weight o protein is 2@@ mg



AFFINITY SCREENING

Drug target

resin

Low binding molecule

High binding molecule

Washing Solution



SURFACE PLAS ON

RESONANCE• *ptical method o detecting when a ligand binds to itstarget

Flo+ o6 5&7 ( %ol& "o$

E*,$ %# $ +,* D ! (,$ L,)

Gol. L,) (

Gl,%% Pl,

o$o#4(om, "#Pl,$ -Pol,(" .

L"'4

Immo5"l". l"',$.

pl,%mo$

8

- ’ ; m ,%&(

D(&',('-o el compound

that binds target

-o el compound

that doesn ‘t bindtarget



ISOLATION ANDPURIFICATION



ISOLATION AND

PURIFICATION• A must i the lead compoundcomes rom a mi ture o othercompounds

• 8ase depends on the structure!stability and uantity o thecompound



STRUCTUREDETER INATION



STRUCTUREDETER INATION• F7ray crystallography

• -' and I spectroscopy• mass spectroscopy



END OF LECTURE

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Drug Discovery Design and Development