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J I.I.Rgen Drew and Tefan Ry Er

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J I.I.Rgen Drew and Tefan Ry Er Ji.i.rgen Drew and tefan Ry er ~ e term "g n mi ·ci n e " land f r the totality falls icntili , llempt t 1 \..,, un er' tand the tructure nd fun ti n f th human g n me an fall Lher genomes. The scientific mission of genomic cience is not defined b the analy is f inglc gene carrying pecific ·tru tural or fun Lion I haractcr ; r ther, gen mi s ·ien es attempts t under tan rhe way in which a p:irLi ular el f gene (3,0 0 in bacte­ ria, ,000 in yeast, approximately 100,000 in humans) contributes to th hape, the func- li n, and the development f whole organism fr m c n eption t death. The pmemial of genomic cien sf r medicine i fourfi ]d: In Lhe fir l place, the knowl­ edg of the gene allcrali n - that cau e di ·ea. will lead t a new unders and in• of "di ea e disp "iti n." Thi knowledge \ ill inc itably lead to n vcl or greatly improved diagnostic method . econd1 the abilit c:onveyed by gi.:nomic iences lo diagno e di e, e di posi- l'i n \ i.11 open Lh d r or preventive meJic. I trategic . Thfrd, gen mi will lead lo th identification o new drug target~. These new drug targets will alJaw the ·ynthe ·is of ·mall mol cu]e with n vel me h ni ms of action. Fin lly, we will be able l relate certain geno­ L)1 e. t the acti n f drug . hi · \ ill all w the cla i 1c.1tion r patient · int group · potential r spondcrs and non responder to already existing and nc, mectications. hile all the e area · are imp rtant L the pharmaceu'li al indu try, the id n1if 1cation of novel drug targets is of particular interest to drug di cover}' 1.::fforts. We bav c ti mated the number f I Len Lia I drug target · · ·pe ted t be tleri ed from gen mi . l e in the r nge 3, 00 to I 0,000'. This estimate i ba ed n the a umpli n that Lher arc ab ut I 00 no. ological entitie that represent ma· r multifacl rial diseas ; Lhal on a erage, c.1ch r the: di ca e i generat •d by contribu i n fr m l gene·; and that ea h r these "<li ea.sc gene "will mnumicatc with many other protein·, 3 to 10 of which ma turn out to be drng targets in an individual cas . Whik the e. trapolali n remain pe ulativc, Lhey ar on Lhe n erv. tive ide, at least with respect l Lhe number f di ·ea,e en Lili thal erved a the ba i · o · this compul:ition. There is no doubt that genomic sci nces c:111 lead to an en m1ou ·pansi n f the numb r r drug targel n which pharma eulical and bi - pharmaceutical omp,1nie will w rk. In contrast, ur cnt therapic a , de cribed in a standard pharm.1 ol g}' texl are ba ~d n n m re Lhan 500 m lecul r drug larget . These target. are presented here becau c lhey r veal what have been hem t fruitfo1 path or therapeutic d vel pm nt in the pa ·t, nnd ive a glimp.e of where genomi . cience may ield drug-di ve1 uc c · in the future. The drug target. are c teg riz d a cording to the therapeutic ureas corresponding to lh section in ,o dman · ilman' · The Pl,nrmocologirnl Ba is o Tl,empeutics'. The distribu- ti n f the targ ts i patch a.nd refle the opp rtuni m that ha l'en e ture or pa ·t pharma euti al vet pment. Drug argec that affe l ·ynapti and neurneffoctor junction si te , as well ,s entrnl ncrv us yslem drug , a c uni f r alm ' t 0% f the t ta\. Alm st half o f Lht! drug targ •t are di ided more or less equall)' bcn cen drugs that acldre inOammati n, renal and ardi vas ul r fun Li n, infe ti u di ease,, or hom1one g nist. and antagonist ·. The re t (26%) ar~ largct JJ b drugs affe Ling I d di ease .• cga 'lr in ­ te ~tinal run ti ns, uterine moliJity, anc itnmunomoclu1ati n • nd by ·lamins in the role f therapeutic·. Th e target · ar ei lh r n liluent [ th hum. n bod (for pham1a­ co I nami thcrap ) or of exogen us . ath or para. ilcs ( in chem U1crapy). We h n b1 - chemi al la. e su h a recepl rs, eni receptor , DNA, and wtlmown . Alrea ay it i evid nl th Jt n rherapie: will irected al • peciric dise,ise target ami me hnn l m , which in tum m on! a egmcnt or a particular di e· e phenol}' e. H w that wil lrug i!l very remains l be een. ln any case, harm ceutical c mp integrate new techn 1 gie. like the i nlifi ti n and hnracterization of ~w tar ct - through genomic cience into Jrn d i b ea trong c mpetiti e d, an t ge in the rulur e. I. Oft'w~ ,. 19 b G,'ll<1mk Klcn,c:s~nd rhc medtdn 11f1omomi l. Gootln-u,n wnJ o1lm•n'• rl,r f'lrnrm11ru/oyiro/ 8nm of TT1tn1pt,.,lo.. 9th · ll-u,. ·I hll. ~ York. Tllrgc:n Oitw< u pr.,..Jdrnt ,if glnhJI r...arcit and 1efan II\...,, i ,:hlcf af i11tcrm1tinm,I ""4:'Jrdi ,ti ~' Hoffmonn·Li ltoch• ltd , I ~,. 'wllnrl~nd. Th ~uthu,.., w ih ltl 1.b,u1I. Y,onnc h;itcr lnr =•<'.'Wing the lllble. - nature biotec ru ~ Target Number c...,ynaptic and Neuroeffector Junctional Sites and Central Nervous System ty pe o f ta rgets 5-hydroxytryptamine selective neurotransmitter/serotonin transporter ............. ... ............ .. C ... .. 1 Acetylcholinesterase .....................•. J ................................ .... .. .. ... .. E . ......1 Adrenergic receptors, a., o:2, p., (32, f3J .... •.....•·• ............................ .• .•... .............R ..... .5 (3-amyloid . .. : . ...... ....... ........... • . ... .. ..... .....E . ...... 1 Benzodiazepine receptor ............. .. • , . , . • . .... .. ..... ....... ... .. .. , . .. .. ..........R : . .. ..1 Bu •• • tyrylcholinesterase ........... 1 • • • / •• .' • • ~ - ••• •• • ••••••• •• ••••• • ••• \ • • ••• •• •••• •• • • ••• • .*.E .......1 1 Ca ' channel . • . '/':. • .... .• • . .................................... -~· . .....c ......1 Catechol-0-methyltransferase . • . •li: .. • ,;•. • • • • . • • . .•.....••......... • •. • • • . •. •...... • • • .•.•E . ...... 1 Cholecystokinin ( CCKA> CCK8) • • , •• •• ; •• •••••• •, • • •••• •••• •• •••••••••• • • •••• • • •••• • • •• • • ••• • R . .....2 Choline acetyltransferase . • . • . • . .. .. ..•. .. .. .. E . .. l Dopamine 1-5, D1-5 ............ ~. ·l ' . .. ..................... .. .. ........ .. ... R .... .5 GABAA receptor 60: variants, 3(3, 26, 3y'o/.iilnt •. ................. ........... ... ... R . ... .14 GABA transaminase . ................... • . ........... •• ..E .......1 Glutamic acid decarboxylase . ... .. ·1· .. .. ... ... .. .. .. .. .... - ... ....E . .. .. 1 g;~:~:~rt:c::,i::;t~:epr~~~~~~r_s'. ~:~· . ~ ~~ . ·• . -.7: ~~~ ~ ~~A: ~'. ~~~~.~ ~~.: :: :: .. ~ ~:::::: : : : : :~~ Histamme, , • • • • • • • • • • • • • .. H., H 2 H 3 ••• 1,.1 ..; .... ..... .. .... ..... .. ,. ... .•. .. ...... .. .. ..R ......3 Ion channel associated with GABA!)~ pfQr. · ~· ·( ·/· .. ... .............. ...... ....... .... , .C .. ....1 Ka inic acid, agonist, a subunit of the Cai+ Qll,m ~-'dependent protein kinase H · ~ . .. •. ... •••• .E . .... •• I Li+ (wtl<nown target, but pharmacologiai,.ly. sped.fl~.) . .. .. .... _. ...U • .... 1 Monoamine oxidase (MAO)-A . ... • •••••. ,. • ~ • .... • • .E . ..... ,J. Monoamine oxidase (MAO)-B .. ..... •• i:-, , •• • • • •• •• .• ••.•••••••••••••.•••••••••• ••••••• • •••• •E . .. .,.. 1 Muscarinic receptor, M 1, 3 subunits ..... .• • !. •• •• •• •• ••••••••••••••••••••••••••••• , •• •• ••• •••• •R .. .- ... 1 Muscarinic receptor, M2 , 3 subunits . • • •••. .. • ............................... •• • •.. .... :'n: Muscarinic receptor, M3 , 3 subunit!. , ••• t •• •.••. ••••• .......•.........•....•.....R Muscarinic receptor, M,i, 3 subu . ~ . ... ,.... ..... , . .. ..... ...... ·.;,,,,.· ......... ....R Na+ channel, a., (3 1, (33 • • • • • • • • • • •• • • ••• • • ~ .. .. • . ... ... ......... ... .. -· • • •• ••••C Neuropeptide Y, Y 1, Y2 . • . • • • .. • •• •• . •• • •• , • • . • • • • • • • • . • . • • • • . • • . • • • 4 • • • ••• • • •• • • •R Nicotinic cholinergic receptors,,usde N M a;~. 8, y, •E • • • • • • •• , • ••••• • •••••...• • .•...• •• • • ••.• •R Nicotinic cholinergic receptors, u~al, NN 0:2, 0:3, a.., <Xs, ~ a-,, <lt!, ~ P2, P3, f34 .•.... .... ••• . ••. R Norepinephrine transporter . •. .. .... .. • ....... .. ...... ....... ...... ...•.•• . • -~ Opioid r eceptors µ1_2 , 81_2 , K 1_3 • • •• • • • •• ••••• •• • •••• • ••••• •• ••• •• • •• •• • •••••••• • ••••••• • • • •• • • • R Phospholipase C11 ............ •.•••• ......... _. ......... : • .... ... ~ . .. .... .............. .E ....... l Purines,_ P 1 (A1,2;1,lb,,), P2x, P2y ... ... ~ - :.· •.., • •.••• • • ...•• •.•• •• , • ••• • •. •. •• • ••• • .•.. ... •.•• .R . .....6 Serotomn 5-HT receptors 5-HTiA-F, 5-H~,,':5-HT4-7 • •• ••••• ••••• • ;:, •• • • •• • •• ••••• •• •• •••••R .... .14 Somatostatin, SRIF LA-e, SRIF?A.B . , • .... ..... .... ~. ... ..•.. : .... .... ..R . .... 5 Succinic semialdehyde dehydrogenase. • •.• . , .. : . • . •. .... ..... ... ...E •••••••1 Tachykinins, NKl, NK2, NK3 ........ ... .... ....... .. .. .• . •• ~.!>-~ ••• • • • ,., • • ••• ••••• •• : • •••R .... ..3 Tryptruninergic receptor ............ ......... ...... .................. ... .. ..., . ........ ....R . ....•2 Vasopressin, VI A,B . ................................................. ....... .. ......... .. R • ..•. .3 Voltage activated ea2+ channel, T-type Ca2+ channel ............ .................... ....... ......C ... L Subtotal (8 C, 12 E, JJS R, I U) . .. .. ... .. .... .. .. .. .. ....... ... ..... .. .. ... .. ..13 6 Jn11ammauon p1 and Pz adrenergic receptor . ... .2 Bradykinin BI and B2 receptors . .....R .... 2 Corticosteroid adrenocorticotropin receptor . • . .R ,• .... 1 Cyclooxygenase l, 2 (COX-1, COX-2) ............................................................E .......2 HistaminereceptorsH1,H2,H3 •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• ••• •R ..... .3 Inorganic acid transport (inhibitor) ............................................................U
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