Drug Discovery and Development - An Overview

8/20/2019 Drug Discovery and Development - An Overview

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DRUG DISCOVERY ANDDRUG DISCOVERY ANDDEVELOPMENT:DEVELOPMENT:

AN OVERVIEWAN OVERVIEW

Prof. K. K. SharmaProf. K. K. SharmaDepartment of PharmacologyDepartment of Pharmacology

University College of Medical Sciences, Delhi-110095University College of Medical Sciences, Delhi-110095



• Development of new drugs/medicines/therapeutic modalities revolutionized the practice of medicine.

• The new medicine discoveries have converted

many once fatal or debilitating diseases intoalmost routine therapeutic exercises.

• Many new drugs have enabled treatments for

diseases that were previously untreatable• Others have expanded the treatment options

because they are more efficacious and/or lesstoxic than previously available treatments.

INTRODUCTION



• or example today deaths fromcardiovascular disease and stro!ehave decreased by almost "#$ or less

over the past %# years• This reduction is due&in part& to the

discovery and increased use of antihypertensives' cholesterol synthesisinhibitors and drugs that prevent ordissolve blood clots.

INTRODUCTION contd…



• he development of a ne! dr"g is diffic"lt and a costly affair#• $ery fe! molec"les that reach the development stage are"ltimately approved as dr"gs, e#g# of 10,000 compo"ndsconsidered promising from the res"lts of initial screeningassays, only 10 ma%e it to clinical trials, and only & are

event"ally approved#• he costs associated !ith discovering and developing a ne!

dr"g can range from 0#' to 1#( )illion dollars#

• *ltho"gh the development of ne! dr"gs is a ris%y vent"re,

s"ccessf"l dr"gs can )e +"ite profita)le for those !ho are!illing to ta%e s"ch ris%#

• he most commercially s"ccessf"l dr"gs, s"ch asatorvastatin, have ann"al sales of more than 1& )illiondollars#

Economics of Drug Discovery & Development



Economic Imac! of Dr"#Economic Imac! of Dr"#

Di$co%&r' an( Dr"# D&%&)om&n!Di$co%&r' an( Dr"# D&%&)om&n!

• World market of pharmaceutical salesamounts to approx. US $ 250 billion

• Expected to gro ith an a!erage rate of "#

% per &ear • US has approx. '0% of orld market

• Europe has approx. 25% of orld market

• (apan has approx.)5% of orld market• *here are currentl& +0 drugs that sell morethan US $ ) billion per &ear, the top to drugsselling almost US $ ' -illion per &ear each.



Th& *+ (r"#$ $&))in# mor& !han , -i))ion US in ,//0Th& *+ (r"#$ $&))in# mor& !han , -i))ion US in ,//0

an% Chemical ame Main indication.s/

, *torvastatinSimvastatin Cholesterol red"ction

1 mepra2ol Ulcers

* 3l"o4etine Depression

2 *mlodipine ypertension and angina

3 6nalapril ypertension and congestive heart fail"re

4 7oratadine *llergies

5 *torvastatin Cholesterol red"ction

0 Sertraline Depression

/ Paro4etine Depression

,+ Con8"gated oestrogens andmedro4yprogesterone

Menopa"sal symptoms and osteoporosis

,, Pravastatin Cholesterol red"ction

,1 *mo4ycillin and -clav"lanate

:nfections

,* lan2apine Psychotic disorders



Th& *+ (r"#$ $&))in# mor& !han , -i))ion US in ,//0Th& *+ (r"#$ $&))in# mor& !han , -i))ion US in ,//0 con!(6.con!(6.

an% Chemical ame Main indication.s/

,4 6poetin alfa *nemia or renal fail"re

,5 7ansopra2ol Ulcers

,0 Cyclosporine Prevention of organ re8ection

,/ anitidine Ulcers

1+ Clarithromycine :nfections

1, Paclita4el varian and )reast cancer11 Ceftria4one :nfections

1* S"matriptan Migraine

12 7isinopril ypertension

13 3ilgrastim e"tropenia

14 3amotidine Ulcers

15 Diclofenac steoarthritis and rhe"matoid arthritis

10 7osartan ypertension

1/ ifedipine ypertension and angina

*+ *2ithromycin :nfections



Di$&a$& Ar&a$ of Dr"#Di$&a$& Ar&a$ of Dr"#

D&%&)om&n!D&%&)om&n!

• 7&$! $&))in# (r"#$ mo$!)' -&)on# !o CVS 8)ii( )o9&rin# h'&r!&n$ion an#ina&c!ori$ h&ar! fai)"r&; CNS 8(&r&$$ion$'cho$i$ mi#rain& &i)&$i&$; GIT 8")c&r$ #a$!ro<&$oha#&a) r&f)"=; an(inf&c!io"$ (i$&a$&$

• I! i$ imor!an! !o no!& !ha! o"! of *+ !o

(r"#$ on)' * ar& -io!&ch como"n($.• No!& a)$o !h& a-$&nc& of (r"#$ for (i$&a$&$

!ha! ar& fr&>"&n! in !h& (&%&)oin# 9or)(

&.#. ma)aria.



Co$! of D&%&)oin# a N&9 Dr"#Co$! of D&%&)oin# a N&9 Dr"#

• Co$!$ of (&%&)oin# a n&9 (r"# ar& &$!ima!&(!o -& -&!9&&n 13+</++ mi))ion US 8'&ar 1+++&$!ima!&$;.

• To(a' !hi$ co$! i$ aro=. ,.1 -i))ion US .

• Pharmac&"!ica) comani&$ $&n! an a%&ra#&,3? of !h&ir $a)&$ on r&$&arch an((&%&)om&n! 8R@D; for -io!&ch comani&$!hi$ fi#"r& i$ 8$om& !im&$; m"ch hi#h&r.

• Man' -io!&ch comani&$ (o no! ha%& $a)&$ '&!ar& financ&( -' !h& incom& from Boin! %&n!"r&$.



DRUG DISCOVERY @ DEVELOPMENTDRUG DISCOVERY @ DEVELOPMENT

• Can -& (i%i(&( in!o !9o -roa( c)a$$&$ ha%in#

$"-c)a$$&$ of !h&ir o9n,. Dr"# Di$co%&r'

a. Tar#&! -a$&( (&$i#n-. Como"n( -a$&( (&$i#nc. L&a( o!imia!ion

1. Dr"# D&%&)om&n!a. Pr&c)inica) Pha$&

Pharmacoin&!ic$ in anima)$ Pharmaco('namic$ in anima)$ 8Anima) mo(&)$ of (i$&a$&$; GLP To=ico)o#' an( Saf&!' $!"(i&$ Ca)c")a!ion of ,$! "man

(o$&-. C)inica) Pha$& Pha$& I C)inica) Tria)$ Pha$& II C)inica) Tria)$ Pha$& III C)inica) Tria)$ Pha$& IV S!"(i&$FTria)$



Dr"# (i$co%&r' Dr"# (&%&)om&n!Pha$& Tar#&!<-a$&( F

Como"n(<-a$&(L&a(o!imia!ion

Pr&<c)inica)(&%&)o<m&n!

Pha$& I Pha$& II Pha$& III

Di$co%&r'Ch&mi$!r'

Di$co%&r'7io)o#'

Tar#&!i(&n!ific

a!ion

A$$a'(&%&)o<

m&n! an($cr&&nin#

Anima) mo(&)$ of(i$&a$&

ADME In %i!rom&!a<-o)i$m

Pharmaco<in&!ic$8anima);

8h"man;

M&!a-o)i$m

Dr"#<(r"# in!&rac!ion$

To=ico)o#' Scr&&nin# Pr&c)inica) GLP!o=ico<

)o#'

Eff&c! on R&ro("c!ion an( Em-r'o<f&!a)D&%&)om&n!

carcino#&n&$i$

D&%&)om&n!ch&mi$!r'

M&(ica) Saf&!'&=o$"r&

Efficac'(o$&$&)&c!ion

R&#i$!ra!ion!ria)$

/1 1

SEQUENCE O !"#SES O DRU$ DISCO%ER & DE%E'O!(ENT



'IE CC'E O DRU$ DISCO%ER) DE%E'O!(ENT & #!!RO%#'

Dr"#(i$co%&r'

81<3 '&ar$;

Dr"# (&%&)om&n!

83</ '&ar$;

Po$!<aro%a)

r&#")a!ion3hem4 -iol

3ompoundidentification 4optimiation

-iologicalcharacteriation

*oxicol

og&

*oxicolog&

studies

3linical INDfi)&(

6h. /trials

6h. //trials

6h. ///

trials

6h./7

6h./7

8anufacturing 1e!elop manufacturing1e!elop 9:93 program;<86 practices

8anufac#turingbegins

Pharmaco<%i#i)anc&ac!i%i!'FPa!&n!&=ir&$FG&n&ric$a%ai)a-)&

=egal Pa!&n!a)ica!ion

Pa!&n! #ran!&(

E

n ( o f P h a $ & I I m & & ! i n #

A N D A f i ) & (

N D A f i ) & ( : R & # " ) a ! o r ' A r % ) f o

r M a r & ! i n #



• -& la safet& andefficac& should be

defined before a drug islicensed for marketing.



ir$! $!& in !h& (r"#ir$! $!& in !h& (r"#

Di$co%&r' i$:Di$co%&r' i$:• the disco!er& or s&nthesis of a

potential ne drug molecule andthen finding its rele!ant biologicaleffect and understanding the

basis of its interaction ithappropriate target structures.



Si= aroach&$ -' 9hich a n&9 (r"#Si= aroach&$ -' 9hich a n&9 (r"#

or (r"# ro("c!$ ar& (i$co%&r&(:or (r"# ro("c!$ ar& (i$co%&r&(:

,. Tra(i!iona) aroach: Screening for biologicalacti!it& of large number of natural products;libraries of pre!iousl& disco!ered:claimedchemical entities or large bank of peptides; nucleic

acid and other organic molecules.

1. Ch&mica) mo(ifica!ion$ of a knon molecule

*. I(&n!ifica!ionF or &)"ci(a!ion of a ne drug

target2. Ra!iona) (r"# (&$i#n of a ne drug molecule

based on an understanding of biologicalmechanisms; drug receptor:target structure; and

drug structure.



Si= aroach&$ -' 9hich a n&9 (r"#Si= aroach&$ -' 9hich a n&9 (r"#

or (r"# ro("c!$ ar& (i$co%&r&(:or (r"# ro("c!$ ar& (i$co%&r&(: con!(6con!(6

3. 7io!&chno)o#ica) aroach using biotechnolog&and cloning to make gene products; like peptidesand proteins. >ecentl& efforts ha!e been made todisco!er ne targets using approaches of

genomics; proteomics nucleic acids and molecularpharmacolog& for drug therap&. -etterunderstanding of disease processes andidentification of culprit molecules has significantl&

contributed for de!elopment of ne and impro!eddrugs.

4. Com-ina!ion of no9n (r"#$ to obtain additi!e ors&nergistic effect or a repositioning of a knon drugfor a ne therapeutic use.



Dr"# Di$co%&r'Dr"# Di$co%&r'• Th& !&rm Dr"# Di$co%&r' i$ (&fin&( a$

!h& roc&$$ -' 9hich harmac&"!ica)aca(&mic or #o%&rnm&n! )a-ora!ori&$i(&n!if' or $cr&&n como"n($ !o fin(

o!&n!ia))' ac!i%& harmaco)o#ica) a#&n!.• Dr"# Scr&&nin# con$i$!$ of !&$!in# man'

como"n($ in an a$$a' r&)&%an! !o !h&

(i$&a$& in >"&$!ion.• A como"n( !ha! a$$&$ !h& $cr&&n i$

ca))&( Hhi! como"n(.



Dr"# Di$co%&r'Dr"# Di$co%&r' con!(..con!(..

• If !h& como"n( or i!$ $!r"c!"ra)(&ri%a!i%&$ con$i$!&n!)' $ho9romi$& af!&r f"r!h&r -io)o#ica) an(ch&mica) charac!&ria!ion i!-&com&$ a H)&a( como"n(.

• I(&a))' (r"# (i$co%&r' $ho")( -&

co$!<&ff&c!i%& an( ro("c& hi!$ !ha!ha%& #r&a!&r )i&)' )&%&) ofcon%&r$ion !o )&a( an( &%&n!"a))'

$"cc&$$f") (r"# for mar&!in#.




• Dr"# (i$co%&r' an( (&%&)om&n! r&main$ a)&n#!h' hi#h ri$ an( com)&= roc&$$

• E%&r' 3<,+ !ho"$an( ch&mica))' $'n!h&$i&(mo)&c")&$ !ha! ar& $cr&&n&( for (&%&)om&n!

on)' on& -&com&$ an aro%&( (r"#.• In 1++, mor& !han *1 (r"#$ an( 0 -io)o#ica)$

r&c&i%&( mar&!in# a"!horia!ion from DA

• O%&r !h& a$! (&ca(&$ !h& DA ha$ aro%&(

aro=. 1++ n&9 (r"#$ an( -io)o#ica)$.• Th&$& n&9 (r"#$ inc)"(& ,13 n&9 mo)&c")ar

&n!i!i&$ 9hich ar& ac!i%& $"-$!anc&$ !ha! ha%&n&%&r "$&(



Dr"# Di$co%&r'Dr"# Di$co%&r' Con!(..Con!(..

• O%&r !h& a$! !9o (&ca(& !h&r& ha%& -&&n maBor chan#&$ in

!h& (r"# (i$co%&r' roc&$$ in !h& harmac&"!ica) in("$!r'.• Thi$ ha$ -&com& o$$i-)& a$ a r&$")! of mo)&c")ar r&%o)"!ion in

-io)o#' an( m&(icin& an( !h& in!ro("c!ion of a 9i(& ran#& ofn&9 !&chno)o#i&$ 8-ioFharmacoinforma!ic$ f)"or&$c&nc&$&c!ro$co' c&)) c")!"r& !&chni>"&$ harmaco#&nomic$

r&com-inan! DNA !&chno)o#' com-ina!iona) ch&mi$!r' &!c.;!h& (r"# (&%&)om&n! roc&$$ ha$ -&com& m"ch$ohi$!ica!&(.

• 7a$&( on !h& m"ch mor& (&!ai)&( "n(&r$!an(in# of !h&a!hoh'$io)o#' of (i$&a$&$ an( on mo)&c")ar -io)o#'

!&chno)o#i&$ n&9 !ar#&!$ 8r&c&!or$ &n'm&$ ion chann&)$#&n&$; ar& i(&n!ifi&( an( a$$a' $'$!&m$ ar& (&%&)o&( !o !&$!)ar#& n"m-&r of mo)&c")&$ from &=i$!in# )i-rari&$ "$in# ro-o!ic$'$!&m.




•Thi$ $o ca))&( hi#h !hro"#h"! $cr&&nin# 8TS; an(")!ra<hi#h !hro"#h"! $cr&&nin# 8UTS; 9i)) i(&n!if'hi!$ i.&. mo)&c")&$ 9i!h r&a$ona-)& affini!' 8-in(in#ro&r!'; !o !h& !ar#&!.

•Th& m&(icina) ch&mi$! !h&n o!imi&$ !h& hi!mo)&c")& aimin# a! ma=ima) o!&nc' an($&)&c!i%i!' an( 9h&n $"cc&$$f") !hi$ 9i)) r&$")! inon& or mor& )&a( como"n($ for !&$!in# in in-vitro $'$!&m.

• NMR J<Ra' cr'$!a))o#rah' ma$$<$&c!ro$co'com"!&r<a$$i$!&( $!r"c!"r&<ac!i%i!' r&)a!ion$hi8CASAR; an( com"!&r<a$$i$!&( mo)&c")ar (&$i#n8CAMD; !&chno)o#i&$ ar& "$&( in )&a( o!imia!ion.




• *o basic strategiesare used to identif& hits.

Como"n(<c&n!&r&( Dr"#D&$i#n

Tar#&!<c&n!&r&( Dr"# D&$i#n




• Dr"# (i$co%&r' ma' -& como"n(<c&n!&r&( or !ar#&!<c&n!&r&( Como"n(<c&n!&r&( Dr"# D&$i#n:

• I(&n!if' como"n(• A$$&$$ -io)o#ica) ac!i%i!'

• Mo(if' como"n( !o incr&a$& ac!i%i!'

Tar#&! c&n!&r&( Dr"# D&$i#n:• I(&n!if' !ar#&!

• D&!&rmin& $!r"c!"r&F(&%&)o a$$a'

• U$& $!r"c!"r&Fa$$a' !o o-!ain Hhi!

• Mo(if' Hhi! !o incr&a$& ac!i%i!'





COMPOUND<CENTEREDCOMPOUND<CENTERED

DRUG DESIGNDRUG DESIGN• /n this strateg&; a compound is

identified b& one of se!eral methods

and its biological profile is explored.• /f the compound displa&s desirablepharmacological acti!it&; it is refined

and de!eloped further.



COMPOUND<CENTERED DRUG DESIGNCOMPOUND<CENTERED DRUG DESIGN

. atural 3ompounds *raditionall& drugs ere disco!ered using a compound

centered approach 8an& of the earliest drugs disco!ered ere natural

products isolated from plants; molds; or other

organisms ?ften; the disco!eries ere made serendipitousl&; e.g.penicillin as disco!ered hen lexander @lemingobser!ed that spores of the contaminant moldPenicillium notatum inhibited bacterial groth in a

petridish. ?ther natural products that ha!e been transformedinto successful drugs include pacilitaxel; achemotherapeutic deri!ed from the 6acific &e tree;morphine; an opioid analgesic obtained from the

opium popp&; streptokinase; a thrombol&tic agentobtained from streptococcal bacteria etc.



COMPOUND<CENTERED DRUG DESIGNCOMPOUND<CENTERED DRUG DESIGNcon!(..con!(..

.atural 3ompounds # there are se!eralad!antages to examining natural products as asource for potential drugs

iA atural products ha!e a reasonable likelohood ofbiologic acti!it&

iiA /t ma& be easier to isolate a compound from itsnatural source that to s&nthesie a compound deno!o; especiall& if the structure of the compound iscomplex or reBuires difficult& s&nthetic manipulationsC6aclitaxel has a complex structure that contains four

fused rings; one of hich contains eight carbons achemical s&nthesis of the compound takes o!er 50steps to complete and has a total &ield of D)%.

iiiA /t ma& be feasible to use the natural compound as a

starting point for s&nthetic fine#tuning; i.e. to for asemi#s&nthetic product.




.atural 3ompounds oe!er; naturalproducts also ha!e disad!antagesF

iA /t often takes significant effort to isolate anatural product; ithout a guarantee of

successiiA lthough natural products are more likel& thanman& s&nthetic compounds to ha!e biologicalacti!it&; it ma& be difficult to predict hich

assa& s&stem ould be optimal for testing thefunction of these molecules.iiiAE!en if it is found to be pharmacologicall&

acti!e; a natural product can be expensi!e toisolate and modif&.




-. S'n!h&!ic Como"n($• *his approach is no freBuentl& used tosearch for ne drugs

• >esearchers can construct a librar&consisting of thousands of compoundsith differing structural characteristicstailored for a particular t&pe of need;

e.g. a librar& could consist of numerouscompounds that ha!e a l&sine#prolineinstead of proline#l&sine bond or thatare likel& agonists or antagonists of a

particular class of receptors.




3. Ana)o#$ of Na!"ra) Li#an($ • n alternati!e compound#centered approachuses the natural ligand of an agonist of areceptor as the starting point for drugde!elopment; e.g. since dopamine deficienc& innigro#striatal s&stem in the brain is associatedith 6arkinsonGs disease; one of the firsteffecti!e treatments; for this disease asadministration of =#dopa; a metabolic precursor

of dopamine .• /nsulin as de!eloped in much the same a&,

once it as disco!ered the signs and s&mptomsof diabetes mellitus ere caused b& lo insulin

le!els; insulin as administered exogenousl&.




3. Ana)o#$ of Na!"ra) Li#an($ • *he atural agonist of a receptor can alsoser!e as a skeleton on hich chemicalmodification can be made.

• Such changes can alter the compoundGsbinding affinit& or ph&siological effect; e.g.agonist con!erting into an antagonist.

• *his approach as used in the de!elopment of

cimetidine an 2

#receptor antagonist fromhistamine:insulin analogs ith differentpharmacokinetic properties.



TARGET<CENTERED DRUG DESIGNTARGET<CENTERED DRUG DESIGN

• /n this strateg&; hich is no the more common mode; the

putati!e drug target is identified first• *he potential target could beF

receptor thought to be in!ol!ed in a disease process; critical en&me; or another biological important molecule in the

disease patha&.

• ?nce the target is identified; researchers search forcompounds that interact ith the target as agonists;antagonists; or modulators.

• *he search ma& be s&stematic; using information aboutthe structure of the target as a starting point; or it ma&

take a shotgun approach; hereb& all the compounds in alarge librar& of compounds; s&nthesied !ia combinatorialchemistr&; are tested in a high#speed automated assa&.



TARGET<CENTERED DRUG DESIGNTARGET<CENTERED DRUG DESIGN

• /n this strateg&; researchers used a !alidatedbiochemical or molecular target to search forhits.

• *his strateg& has se!eral ad!antagesi. /f the target has been associated ith a disease process;

a hit that successfull& interacts ith the target has arelati!el& high likelihood of useful pharmacologicalacti!it&

ii. -ecause the target is knon; it ma& be easier to de!iseassa&s capable of isolating effect of an agent on the

target. *his is speciall& true for diseases too complex toobser!e in cell or tissue preparations; e.g. a potentialdrug effect on the process of anthersclerosis ma& bedifficult to measure rapidl&; it is relati!el& eas& tomeasure hether the drug inhibits an en&me shon tobe in!ol!ed in the pathogenesis of this disease such as8<#3o reductase.



TARGET<CENTERED DRUG DESIGNTARGET<CENTERED DRUG DESIGN con!(..con!(..

• s knoledge of the patho#ph&siolog& ofdisease processes has increased; target#centered approaches to drug disco!er& ha!ebecome increasingl& successful and man&ne drugs ha!e been disco!ered using target#

centered methods.• /7 protease inhibitors; such as ritona!ir; are

notable examples of a drug class disco!ered.• /n an alternati!e approach; the de!elopment

of macromolecules; including antibodies; asno!el pharmaceuticals to interrupt thepatha&CsA in!ol!ed in different diseaseprocess.




• igh#*hroughput Screening C*SA *he simplest target#centered approach uses a

rapid screening of man& molecules b& emplo&ingan essa& based on the drug#target

*S uses a target#based assa& and robotic

automation to test thousands of compounds in afe da&s. *o aspects are critical in this approach

i. A )ar#& )i-rar' of como"n($ m"$! -& a%ai)a-)& for$cr&&nin#

ii.A ro-"$! a$$a' !ha! )&a($ !o rai( i(&n!ifica!ion of!r"& hi!$ m"$! -& (&%&)o&(. Th& a$$a' ma' -& a$$im)& a$ (&!&rminin# !h& -in(in# affini!' of (r"#can(i(a!&$ for a r&c&!or or i! ma' -& mor&$ohi$!ica!&( in%o)%in# com)ica!&( -ioch&mica) or

c&))<-a$&( mani")a!ion$.




• igh#*hroughput Screening C*SA n assa& performed in a HI# or +'#ell plate allos

researchers to screen man& compounds simultaneousl&. /n addition; once a librar& of compounds has been

established; the same librar& can be run through man&different assa&s.

*he Bualit& of assa& results is dependent on the assa&methodCsA and the compounds in the librar&; so a poorl&designed assa& or a limited librar& ma& result in falsehits or miss !iable candidates.

/n practice; because *S places a premium on rapidassa&s; false J!e and false !e are not uncommon,besides hen a true hit is found it is most likel& berefined to increase its bind affinit& or to change itspharmacological properties Cspefificit&; solubilit&; stabilit&;kinetic; etc.A.

*his process is called hit#to#lead de!elopment




•3ombinatorial 3hemistr& ?ne important refinement in the process of *S

has been the introduction of combinatorialchemistr&

*his is a strateg& analogous to that used b&nature to construct a ide !ariet& of proteinsfrom a relati!el& small number Capprox. 20A ofamino acids

ere researchers use a relati!el& small number

of precursor molecules to generate a largenumber of compounds; e.g. a researcherstarting ith + sets of +0 precursor buildingblocks can create 2";000 C+0x+0x+0A can createto s&nthetic steps.




•3ombinatorial 3hemistr& ?ne could theoreticall& create each compound

indi!iduall& in its on reaction ell; but inpractice it is easier to s&nthesie the moleculeson a solid support such as a pol&st&rene bead.

/n a parallel s&nthesis; the beads are split sothat thousands are reacted at once and thensuccessi!el& recombined and split to undergosuccessi!e reactions.

*his strateg& drasticall& reduces the number ofreactions in the s&nthesis C+0 at a time insteadof 2";000 at a timeA.




• Structure#based design : >ational drugdesign /n some target#centered strategies called Structure#

based design : >ational drug design; a drugcandidate is disco!ered using the three#

dimensional structure of the target obtainedthrough 8> or K#ra& cr&stallograph& /n theor&; one could identif& the acti!e site ithin

the structure of the target; use modeling algorithmsto stud& the shape of the acti!e site and design a

candidate drug molecule to fit into the acti!e site. 8ore commonl&; though; the target is co#

cr&stallied ith a substrate analogue or receptorligand Cagonist:antagonistA in order to identif& thestructure of the acti!e site.




• Structure#based design : >ational drug design

*he structure of the analogue is then modified toincrease the moleculeGs affinit& Cas as done inthe case of ritona!irA

lternati!el&; one can refine the structure of ane compound that binds to the target in ascreening assa&.

-& iterati!el& impro!ing the fit of the protot&picmolecule in the acti!e site of the target; thebinding affinit& is increased.

*here are se!eral ad!antages to a structure#based drug design approach e.g. the refined hitCalso called leadA compounds are oftenextremel& potent; ith binding affinities in the

nanomolar range.




• Structure#based design : >ational drug design

8oreo!er; onl& a limited number compounds needto be tested because there is a high likelihood thatone or more of the designed compounds ill bindthe target.

/n addition; iterati!e modification of the compound

is relati!el& straightforard because it is knonhich parts of the molecule are critical for bindingto the acti!e site of the target.

*hus; in comparison to a structure#basedapproach; feer analogues are prepared in astructure#based approach but each analogue has ahigher likelihood of acti!it&.

Structure#based methods ha!e also been used tode!elop a ne class of anti!iral drugs; the

neuroaminidase inhibitors C?seltami!ir, Lanami!irA.





7in(in# of Ima!ini- 9i!h -cr<a-) ro!&in for7in(in# of Ima!ini- 9i!h -cr<a-) ro!&in for

inhi-i!in# ho$hor')a!ion of !'ro$in& ina$&inhi-i!in# ho$hor')a!ion of !'ro$in& ina$&

C f ,



Cr'$!a) $!r"c!"r& of IV<, ro!&a$&Cr'$!a) $!r"c!"r& of IV<, ro!&a$&

&n'm& -o"n( -' Ri!ona%ir &n'm& -o"n( -' Ri!ona%ir



LEAD OPTIMIATIONLEAD OPTIMIATION

• *he earl& drug disco!er& process ill t&picall&

identif& a promising groups of lead molecules thatappear to interact ith the target in a desirable a&.• @or these promising molecules; hoe!er; man& of

the ph&sical; chemical; biological andpharmacological properties that are importantattributes of an effecti!e drug remain unknon

• =ead optimiation is the stage of drug disco!er&here these properties are characteried andrefined; ith the ultimate goal of selecting a single

molecule to enter into clinical testing and formaldrug de!elopment; e.g. a number of precursors ofritona!ir ent through se!eral modifications beforea final compound as chosen to enter clinical trials.



LEAD OPTIMIATIONLEAD OPTIMIATION con!(..con!(..

• !ariet& of factors ma& cause a molecule to be

terminated at the lead optimiation stage. *heseincludeF @ailure to demonstrate efficac& in a rigorous animal

model of human disease @ailure to attain adeBuate s&stemic exposures folloing

oral administration Clo bioa!ailabilit&A Extensi!e or complex metabolism ithin the bod&;

resulting in the generation of potentiall& dangerousreacti!e metabolites

Extremel& lo solubilit& that pre!ents preparing a

suitable formulation for dosing *oxic effects in preliminar& animal toxicolog& studies /n !itro e!idence that the molecule ma& damage 1

Cgenotoxicit&A Extremel& difficult chemical s&nthesis that cannot be

Mscaled upN in a cost#effecti!e manner.





PASES O DRUG DEVELOPMENTPASES O DRUG DEVELOPMENT

• *he outcome of the lead optimiation process is the

selection of a molecule suitable for testing in humans• t this point; the molecule mo!es from drug disco!er&to drug de!elopment

• Earl& drug de!elopment consists of preclinicalacti!ities designed to support clinical trials and clinicaldrug de!elopment

• *he initial preclinical phase of drug de!elopmentincludes the folloing acti!itiesF 8anufacture; formulation; and packaging of high Bualit&

drug for both the animal safet& and clinical trial use nimal toxicolog& and pharmacokinetic studies tosupport the safet& of initial drug administration inhumans

6reparation of regulator& documents for submission to

regulator& authorities.

KEY DISCIPLINESFEJPERTISE NEEDEDKEY DISCIPLINESFEJPERTISE NEEDED



KEY DISCIPLINESFEJPERTISE NEEDEDKEY DISCIPLINESFEJPERTISE NEEDED

IN DRUG DISCOVERY ANDIN DRUG DISCOVERY AND

DEVELOPMENTDEVELOPMENT

). 1isco!er& 3hemistr&2. 1isco!er& -iolog& C-iochemcial assa&s;

3ellular assa&s and nimal modelsA+. bsorption; 1istribution; 8etabolism and

Excretion C18EA studies'. *oxicolog&

5. 1e!elopmental 3hemistr&F 3hemical s&nthesis;Scale#up and 8anufacturingI. @ormulation CEnteral : 6arenteral : =ocal :

Specific 1rug 1eli!er& 8odalitiesA




•A)ica!ion of CAMD U$in# r&c&!or<-a$&( ro&r!i&$ 8-in(in# affini!'

an( r&c&!or $&)&c!i%i!'; CAMD ca)c")a!&$ !oroo$& a -roa( ran#& of ro&r!i&$ !ha! ar& )i&)'!o -& "$&f") in (r"# (&$i#n from h'$ica)

ro&r!i&$ )i& mo)&c")ar $i& $o)"-i)i!'in(ica!or$ of m&!a-o)ic fa!& an( !o=ici!' &!c.

CAMD i$ a)$o a)i&( !o fin( an( %a)i(a!& !h&&)&m&n!$ of R")& of fi%& or Liin$i$ r")&. A$ &r

!hi$ r")& a (r"# )i& como"n( )oo$ )i& amo)&c")& 9i!h a mo)&c")ar 9&i#h! 3++ O N#ro"$ )&$$ !han 3 !h& $"m of N an( O a!om$ )&$$!han ,+ an( )o# P %a)"& )&$$ !han 3 for a -&!!&ra-$or!ion in !h& in!&$!in&.



M " ) ! i

< ! a $ D i n

# i $

! h & n

& 9 m a n !

r a



S&stematic high throughput separationand characteriation of proteins ithin

biological s&stems# PROTEOMICS6rotein le!el of disease manifestations

identified

1iagnostics; *arget disco!er&; *arget!alidation; =ead compound selection;/n!estigation of mode of action; *oxicolog&and 3linical de!elopment

TARGET IDENTIICATIONTARGET IDENTIICATION

TARGET IDENTIICATION INTARGET IDENTIICATION IN



TARGET IDENTIICATION INTARGET IDENTIICATION IN

GENE 7ASED TERAPYGENE 7ASED TERAPY

Up to )0 genescontribute to multi#factorial diseases

1isease genes arelinked in circuit5000#)0;000 potential

drug targets

3urrent drug therap&based on D500molecular targets

N&9 !&chni>"&$ of !ar#&!



N&9 !&chni>"&$ of !ar#&!i(&n!ifica!ion aim a!<(i$co%&rin# n&9 #&n&$ @

ro!&in$ an( >"an!if'in# @ana)'in# !h&$&ro!&in$F#&n&$

Ro-o!ic$ in%o)%&$ a"!oma!ion<$i#nifican! incr&a$& in !h&n"m-&r of &=&rim&n!$ !ha! can-& con("c!&(

Informa!ic$ in%o)%&$ !h& a-i)i!' !o!ran$form ra9 (a!a in!o

m&anin#f") informa!ion an(no9)&(#& -' a)'in#com"!&ri&( !&chni>"&$ formana#in# ana)'in# an(in!&rr&!in# (a!a



7IOINORMATICS F7IOINORMATICS F

PARMACOINORMATICSPARMACOINORMATICS8ining of data to extract rele!ant biological :

pharmacological information

3omparison algorithms

• -ase pairs C-=S*; @S*; 6S/#-=S*;6/#-=S*A; 8ultiple seBuence C88E>A

9uantif&ing degree of similarit& beteenseBuences#Scoring matrices



TARGET VALIDATIONTARGET VALIDATION/n!ol!es demonstrating rele!ance of the

target protein in a disease processOnock#out ####loss of functionOnock#in####### gain of function/nhibitors; agonists; antagonists

ntisense nucleic acid constructsot all target proteins are rele!ant6rotein structure information CK#ra&; 8>A help

to predict Mdrug#abilit&N of the protein



Como"n($ ar& i(&n!ifi&( 9hich in!&rac! 9i!h !h& !ar#&! ro!&in$an( mo(")a!& i!$ ac!i%i!'

Ran(om 8Scr&&nin#; Ra!iona) 8D&$i#n;

Na!"ra) como"n($ S!r"c!"ra) 7io)o#'

D&ri%a!ia!ion Mo)&c")ar mo(&)in#

Com-ina!oria) Li-rar' (&$i#n

Ph'$ico<ch&mica) aroach&$

LEAD IDENTIICATIONLEAD IDENTIICATION

IG TROUGPUT SCREENINGIG TROUGPUT SCREENING



IG TROUGPUT SCREENINGIG TROUGPUT SCREENING

• *hroughput speed of screening compounds

• )0;000:da&#######*S• )00;000:da&#####U*S

• dapted assa&s 8ix and measure#a!oid filtration; separation; ash

P= to nano=

HI

)5 +

I

+'

+'5I

TS CARACTERISTICSTS CARACTERISTICS




utomation 8iniaturiation 3ellular assa& s&stem

impro!ements

3omputational methodsfor assa& simulation

1ata management

impro!ements andinno!ations




/ncrease in compoundlibrar& di!ersit& and sie

/ntegrated s&stems

Exponential increase intargets fromgenomics:proteomics

?utsourcing and

customiation






Pi&!!in# Li>"i( (i$&n$in#Mi=in# i)!ra!ionCoo)in#

Mo(")arFIn!&#ra!&(O&nFC)o$&(

S!an(ar(i&(FC"$!omi&(




8ore sensiti!e and efficient assa& anddetection s&stems

Sensiti!e alternati!es to radioacti!e

assa&s

=ead optimiation tools



UTSUTS

• K&' &a!"r& Po$i!i%& N&#a!i%&

Minia!"ria!ion Sa%&$ )i#an( R&forma!

P)a!& forma! Inc $am)& $i& Pr&ci$&han()in#

L>( han()in# Pi&o&)&c!ric C&)) han()in#

A"!oma!ion a%ai)a-)& S&a)&(

Da!a m#m! i amo"n! Inc &ffor!



LIMITATIONS O TS



3onducted in 500 labs

orldide3oordination of technolog&;

processes and people6ermanent need to suppl&Storage 4 retrie!al at #20°3;

constant humidit&=o !olume liBuid handling

6ositional accurac& of roboticarm>epair#cost; time lost Muman attentionN

nal&ing data

LIMITATIONS O TS

TS



TS

7ioch&mica) C&))<7a$&(

>adioacti!e @luorescenceScin!i))a!ionPro=imi!'

A$$a'

)"or&$c&nc& R&$onanc& En&r#' Tran$f&r )"or&$c&nc& Po)aria!ion

omo#&no"$ Tim& R&$o)%&( )"or&$c&nc&)"or&$c&nc& Corr&)a!ion S&c!ro$co'

S&con( m&$$&n#&r a$$a'R&or!&r #&n& a$$a'

C&)) ro)if&ra!ion a$$a'

)"or&$c&nc& R&$onanc& En&r#' Tran$f&r



)"or&$c&nc& R&$onanc& En&r#' Tran$f&r8RET; T&chni>"&

T9o (iff&r&n! chromohor&$ in!&rac! %ia (io)&<(io)&m&chani$m$

E=ci!&( chromohor& !ran$f&r$ i!$ &n&r#' !o acc&!or 7o!h (onor an( acc&!or $ho")( -& in c)o$& ro=imi!' Monoc)ona) an!i-o(' 8C'3; in!&r)&"in , r&c&!or

8&"roi"m ch&)a!&;<<<<$!a-)& com)&=

NATURAL PRODUCTS OR LEAD



NATURAL PRODUCTS OR LEADIDENTIICATION

Secondar& metabolites of plants; microbes;animals

6ro!ide di!ersit&

/dentif& ne targets e molecules acting on knon targets

3hromatographic separation C6=3; 6*=3; =3#

8S; />;; 8>A

SOLID PASE EJTRACTIONSOLID PASE EJTRACTION



SOLID PASE EJTRACTIONSOLID PASE EJTRACTION

6ol&st&rol basedresins allochromatographic

fractionationthrough !ariationof the organicsol!ent

1oes not need6=3



VIRTUAL SCREENINGVIRTUAL SCREENING

/n !i!o#######/n !itro ########/n silico

+#1 structures of compounds from!irtual:existing libraries are dockedon binding sites of target proteins

Steric and electrostaticcomplementarit&

ttracti!e; cost effecti!e before

cumbersome s&nthesis*ime:Structure:3omputer processor

6aralleliation increases throughput



ITS AND LEADSITS AND LEADS

6harmacod&namic properties

efficac&; potenc&; selecti!it&

6h&sicochemical properties=ipinskiGs rule of fi!e; ater solubilit&; chemical stabilit&

6harmacokinetic properties6ermeabilit& in the 3aco#2 assa&; metabolic stabilit&; toxicolog&

3hemical ?ptimiation potentialEase of s&nthesis

6atentabilit&e structures



LIPINSKI$ RULELIPINSKI$ RULE

8olecular eight D 500

3alculated log 6D5

umber of h&drogen bond donorsD5

umber of #bond donors Jumber of #bond acceptors D)0



3hemical modification and pharmacologicalcharacteriation of lead

o9 !o mo(if' )&a(

SAR

LEAD OPTIMIATIONLEAD OPTIMIATION

SARSAR



SARSAR

'0 &ears ago; ansch; @uQita et al in!ented the

field of 9S>Whole molecule parameters like Cpartitioning;

molar refracti!it&; shape; topolog& indicesA for

groups of related compounds are statisticall&correlated ith measures of biological acti!it& toobtain 9S> eBuation

6redicti!e for 3Es that ma&:ma& not exist

1ifficult& of in!erting 9S> into better drugs

SARSAR



> e d u n d a n c &

=e a d m o n o m e r s

6rotein#ligand interaction; shape; energetics;

h&drophobicit&; sie; bonding; flexibilit&



W lik f



•We are like four-year

old child attempting toread and comprehenda Shakespearean

masterpiece. We arenot wholly illiterate,

but we still have muchto learn.



Thank youThank you

i#h<!hro"#h"! Scr&&nin# 8TS;i#h<!hro"#h"! Scr&&nin# 8TS;



i#h<!hro"#h"! Scr&&nin# 8TS;i#h !hro"#h"! Scr&&nin# 8TS; In %i!ro Q 7io)o#ica) Charac!&ria!ion of NCE$FNME$In %i!ro Q 7io)o#ica) Charac!&ria!ion of NCE$FNME$

• Sim)&$! !ar#&!<-a$&( aroach in%o)%&$ rai($cr&&nin# of man' mo)&c")&$ "$in# an a$$a'-a$&( on (r"# !ar#&!.

• TS "$in# ro-o!ic a"!oma!ion a))o9$ !h& rai(

$cr&&nin# of !ho"$an($ of como"n($ >"ic)'.• T9o a$&c!$ ar& cri!ica) in !hi$ aroach. ir$!

a )ar#& )i-rar' of como"n($ m"$! -& a%ai)a-)&for $cr&&nin# $&con( a ro-o! a$$a' !ha! )&a($

!o i(&n!ifica!ion of r&a) hi!$ m"$! -& (&%&)o&(• Th& a$$a' ma' -& a$ $im)& a$ a $!"(' !o(&!&rmin& !h& -in(in# affini!' of NCEFNMEcan(i(a!&$ for a r&c&!or or ma' -& mor&$ohi$!ica!&( in%o)%in# mor& com)ica!&(

-ioch&mica) or c&))<-a$&( mani")a!ion$.




• Th& )i-rar' of como"n($ i$ r"n !hro"#h !h&a$$a' an( an' hi!$ ar& &=amin&( mor& c)o$&)'.

• An a$$a' r"n in a /4 or *02 9&)) )a!& a))o9r&$&arch&r$ !o $cr&&n a! )&a$! /4 or *02NCEFNIMES $im")!an&o"$)'.

• An' NCEFNME !ha! ro("c&$ a hi! ma' (i$)a'"$&f") harmaco)o#ica) ac!i%i!' -&ca"$& i!$-io)o#ica) !ar#&! i$ "$&( !o $cr&&n for hi!$.

• Man' (iff&r&n! a$$a'$ $'$!&m$ can -& "$&( !o$cr&&n for a %ari&!' of harmaco)o#ica) ac!i%i!i&$.

i#h<!hro"#h"! Scr&&nin# 8TS;i#h<!hro"#h"! Scr&&nin# 8TS;In %i!ro Q 7io)o#ica) Charac!&ria!ion of NCE$FNME$In %i!ro Q 7io)o#ica) Charac!&ria!ion of NCE$FNME$




• Th& >"a)i!' of r&$")!$ i$ (&&n(&n! on !h&>"a)i!' of a$$a' an( !h& n"m-&r of NCE$FNME$in !h& )i-rar' $o !ha! a )imi!&( )i-rar' or aoor)' (&$i#n&( a$$a' ma' r&$")! in fa)$& hi!$or ma' mi$$ a "$&f") NCEFNME.

• 7&ca"$& TS )ac&$ a r&mi"m on fa$!a$$a'$ fa)$& o$i!i%& an( fa)$& n&#a!i%&$ ar&)i&)' &%&n if a hi! i$ fo"n(. I! 9i)) mo$! )i&)'n&&( !o -& r&fin&( !o incr&a$& i!$ -in(in#affini!' or !o chan#& i!$ harmaco)o#ica)ro&r!i&$ 8$&cifici!' $o)"-i)i!' in&!ic$ &!c.;Thi$ roc&$$ i$ ca))&( hi!<!o<)&a( (&%&)om&n!.

i#h<!hro"#h"! Scr&&nin# 8TS;i#h<!hro"#h"! Scr&&nin# 8TS;In %i!ro Q 7io)o#ica) Charac!&ria!ion of NCE$FNME$In %i!ro Q 7io)o#ica) Charac!&ria!ion of NCE$FNME$

L&a( O!imia!ionL&a( O!imia!ion



L&a( O!imia!ion&a( O! a! o

• Onc& a hi! ha$ -&&n i(&n!ifi&( m"chr&main$ !o -& (on& !o r&fin& i!$charac!&ri$!ic$ an( #a!h&r informa!iona-o"! i!$ h'$icoch&mica) -io)o#ica)

an( harmaco)o#ica) ro&r!i&$.• Mo$! )&a( NCE$FNME$ ha%& on& or

mor& charac!&ri$!ic$ 8oor

harmacoin&!ic$ (iffic")!' ina(mini$!ra!ion !o=ici!' &!c.; !ha! ma&!h&m oor can(i(a!&$ for c)inica) "$&.

L&a( O!imia!ionL&a( O!imia!ion con!(..con!(..



L&a( O!imia!ion con!(..

• o9&%&r i! i$ in%aria-)' o$$i-)& !o

mo(if' !h& $!r"c!"r& of Hhi! NCEFNME !oo%&rcom& !h&$& (&fici&nci&$

• or &=am)& r&c"r$or$ of ri!ona%ir 9&n!!hro"#h $&%&ra) mo(ifica!ion$ -&for& a

fina) como"n( 9a$ cho$&n !o &n!&rc)inica) !ria)$.

• Th& roc&$$ in 9hich !h& informa!ion i$

#a!h&r&( ("rin# !h& (iff&r&n! ha$& of(r"#<(&%&)om&n! !o mo(if' !h&charac!&ri$!ic$ of a (r"# can(i(a!& i$ca))&( )&a( o!imia!ion.



REERENCESREERENCES

illisch ; ilgenfeld > eds. 8odernmethods of drug disco!er&. Siterland F-irkhauser 7erlag; 200+.

8illigan <. igh content assa&s for ligandregulation of <#protein#coupled receptors.1rug 1isc *oda& 200+, F 5"H#55.

Wolcke ( 4 Ullmann 1. 8iniaturied *S

technologies#u*S. 1rug 1isc *oda&200), IF I+"#I'I.

Pha$&$ of r&<c)inica) an( c)inica) (r"# (&%&)om&n! an(Pha$&$ of r&<c)inica) an( c)inica) (r"# (&%&)om&n! an(!imin# of !h& maBor (&ci$ion$ oin!$!imin# of !h& maBor (&ci$ion$ oin!$



# B

Phase ofdevelopment

Ma8ordecisionpoints

Minor o)8ectives St"dy pop"lation

PreclinicalPhase 0

Start ofdevelopment

Safety in animalsP in animals In vitro meta)olism

*nimals

ClinicalPhase :

6ntry intoman

olera)ilitySafetyP PD .!hen possi)le/

Us"ally healthy male vol"nteers3or inherently to4ic compo"ndspatients .e#g# anti-t"mo"r agents/

Phase :: 6arly efficacy or proof ofconceptDose regimen for phase ;SafetyP

Patients !ith the targeted disease,"s"ally e4cl"ding those !ithcomplications or concomitantconditions

Phase :::a 3"ll

development

Confirmation of efficacy

and safety .)enefit-ris%/Comparison !ith standardtherapy7ong-term safety

Patients !ith the targeted disease,

incl"ding .as m"ch as possi)le/those !ith complications and orconcomitant conditions

Phase :::) Pre-D* 3"rther profiling of thecompo"nd

Patients< seldom healthy vol"nteers

Phase :$ 7a"nch :nvestigator-driven st"dies

7ocal mar%eting s"pportst"dies

Patients< seldom healthy

vol"nteers#

Anima) To=ico)o#'Anima) To=ico)o#'



#'#'• Pr&<c)inica) F non<c)inica) !o=ici!' $!"(i&$

S'$!&mic !o=ici!' $!"(i&$• Sin#)&<(o$& !o=ici!' $!"(i&$

• R&&a!&( (o$& !o=ici!' $!"(i&$ Th&$& $!"(i&$ ar& con("c!&( a$ ac"!& 812 h; $"-<ac"!& 1<* 9$; an(

chronic 8* Q 4 mo;

In ac"!& $!"(i&$ (o$& ran#in# $!"(' i$ con("c!&( !o i(&n!if' !h& !ar#&!or#an !o=ici!' an( &$!a-)i$hm&n! of MTD for $"-$&>"&n! $!"(i&$.

• R&ro("c!ion !o=ici!' $!"(i&$ Ma)& an( &ma)& f&r!i)i!' !o=ici!'

P&rina!a) !o=ici!' $!"('

• D&%&)om&n!a) 8!&ra!o#&nici!'; $!"('

• Dr"# a))&r#'

• G&no!o=ici!' F m&!a#&nici!'• Carcino#&nici!'

Loca) !o=ici!' Q (&rma) a))&r#' (&rma) ho!o<!o=ici!'ora) r&c!a) an( %a#ina) !o=ici!' oc")ar !o=ici!'inha)a!iona) !o=ici!'

Anima) Pharmaco)o#'Anima) Pharmaco)o#'



#'#'• G&n&ra) harmaco)o#ica) ac!ion$

E$$&n!ia) $af&!' !o=ico)o#' Eff&c! on CVS

Eff&c! on CNS

Eff&c! on ANS

Eff&c! on R&$ira!or' $'$!&m

Eff&c! on GI $'$!&m

Eff&c! on G&ni!o<"rinar' $'$!&m

Eff&c! on o!h&r or#an $'$!&m$ 8$&)&!a)m"$c)& -on&$ imm"n& an( &n(ocrin&f"nc!ion$;

Documents

Drug Discovery and Development - An Overview