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8/20/2019 Drug Discovery Design and Development
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DRUG DISCOVERY: FINDING A LEAD
PH CH 129 AY 2010-2011
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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.
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OUTLINEI. #he $rug $isco ery %rocessII. $rug &creening 'ethodsIII.Isolation and %uri cationI(.&tructure $etermination
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THE DRUG DISCOVERY
PROCESS
Compl !T"m
#o$%&m"$'
V ()!p $%"
*
V () lo+%&## %%
(,
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THE DRUG DISCOVERY PROCESS
%rogram&election
#argetIdenti cati
on and(alidation
)eadIdenti catio
n
)ead*ptimi+ation
%reclinical and
,linical&tudies
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THE DRUG DISCOVERY PROCESSP(o'(,
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• ,lear strategy is needed:• -ew agents must ha e statistically pro en
clear ad antages o er e isting therapy• ,onsiderations:
• the medical need• a ailability o current therapy• competitor acti ity•
commercial opportunity
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THE DRUG DISCOVERY PROCESSP(o'(,
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AIN APPROACHES FOR TARGETIDENTIFICATION• 'olecular %ro ling
• /enomics• %roteomics
• 0ioin ormatics• orward and e erse /enetics
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THE DRUG DISCOVERY PROCESSP(o'(,
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AINAPPROACHESFOR TARGETVALIDATION• /ene 3noc3out
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THE DRUG DISCOVERY PROCESSP(o'(,
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AINAPPROACHESFOR TARGETVALIDATION• -A inter erence
4 -Ai5
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THE DRUG DISCOVERY PROCESSP(o'(,
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6its$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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THE DRUG DISCOVERY PROCESSP(o'(,
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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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THE DRUG DISCOVERY PROCESSP(o'(,
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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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THE DRUG DISCOVERY PROCESSP(o'(,
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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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THE DRUG DISCOVERY PROCESSP(o'(,
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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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THE DRUG DISCOVERY PROCESSP(o'(,
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• %reclinical studies in ol e in vitro studies andtrials on animal populations
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THE DRUG DISCOVERY PROCESSP(o'(,
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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 $iagnostic trials: nd better tests or procedures or
diagnosing a disease.=5 &creening trials: test methods o detecting diseases.
<5 >uality o )i e trials: e plore ways to impro e com ortand uality o li e or indi iduals with a chronic illness.
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DRUG SCREENINGETHODS
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SCREENING OF NATURALPRODUCTS
•?@ o the worldBs population uses drugs e clusi ely rom naturalsources.
• "< o drugs contain CprinciplesB 43ey structure elements5 onatural origin.
• )ess than < o the <@@!@@@ higher plant species ha e undergone
biological pharmacological screening.• 8ach plant has potentially 1@!@@@ diferent constituents.
8 tractmi ture
s
0iological
#est
%uri y
eDect
)8A$,*'%*E-$El&#".,
% (&# &(
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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$80ra+ilian iper enom 7 A,8
inhibitor
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PROBLE S 3ITH NATURALPRODUCT SCREENING
– Isolation o an acti e component present in a erysmall amount can be
– problematic gi en a large amount o bac3ground9rubbish .
– #he mi tures are o ten ery comple and containmany large macromolecules. #hese can o ten 9hide
biological acti ity. – ,ompound isolation and structure determination
di cult. – &tructures o ten comple ! there ore di cult to
synthesise and identi y the pharmacophore.
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SYNTHETIC
CO POUNDLIBRARY • a collection o compounds whose ariety 4di ersity5maybe: – small and ery limited 4e.g. departmental library5!
– big but relati ely limited 4e.g. Eni ersity academiclibrary5!
– big and di erse 4e.g. city library5.• those rom past proDects are 3ept and may be screened
or the biological acti ity you are loo3ing or in a newproDect
• -ew compounds may also be made 9in7house butnowadays specialist chemical companies are o tencontracted to simply ma3e -,8s 4new chemical entities5
or big pharmaceutical companies.
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SYNTHETIC
CO POUNDLIBRARY • D"%,.*,$ ,' : 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?
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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
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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
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IN VITRO TESTS• 8 amples: – 8n+yme inhibition
studies – ,ytoto icityassays
–eceptorAgonistsHAntagonis
t #esting – adioligand
studies
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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
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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
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TEST VALIDITY • (alidity o some test procedures
are easy and clear cut• En ortunately some tests are not
clear cut
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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
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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
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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 "$
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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#&
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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$: –
At least the weight o protein is 2@@ mg
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AFFINITY SCREENING
Drug target
resin
Low binding molecule
High binding molecule
Washing Solution
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SURFACE PLAS ON
RESONANCE• *ptical method o detecting when a ligand binds to itstarget
Flo+ o6 5&7 ( %ol& "o$
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
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ISOLATION ANDPURIFICATION
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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
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STRUCTUREDETER INATION
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STRUCTUREDETER INATION• F7ray crystallography
• -' and I spectroscopy• mass spectroscopy
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END OF LECTURE