ABSTRACT
RI WKH WR[LF PDQLIHVWDWLRQV WKDW IROORZ VXOIXU PXVWDUG d $UP\GHVLJQDWLRQ+'H[SRVXUHKDYHEHHQGHÀQHGWKHDFWXDO ORJ\UHPDLQHOXVLYH0XFKRIWKHUHVHDUFKLQWKLVDUHDKDVEHHQ UPDFRORJ\DQG'UXJ$VVHVVPHQW'LYLVLRQVRI WKH86$UP\
VWLWXWHRI&KHPLFDO'HIHQVH86$05,&'WKHODERUDWRULHVRI ODERUDWRULHVIXQGHGWKURXJKWKH0HGLFDO5HVHDUFKDQG0DWHULDO 0&H[WUDPXUDOFRQWUDFWSURJUDP%DVHGRQWKHWHFKQRORJLFDO KURXJKWKLVSURJUDPZHKDYHEHHQDEOHWRJHQHUDWHDXQLI\LQJ DU DQG WLVVXH HYHQWV WKDW H[SODLQV WKH IRUPDWLRQRI FXWDQHRXV
EOLVWHUVIROORZLQJH[ ODWLRQRI FHOOXODUPD SRO\$'3ULERVHSR SURWHRO\WLFDFWLYDWLRQ RIVL[VWUDWHJLHVIRUW SKDUPDFHXWLFDOVWUDW 3$53 LQKLELWRUV FD FRPSRXQGV
7KHVHFRPSRXQG VXUHVDJDLQVW+'GH IRUFRPSRXQGVFUHH F\WRWR[LFLW\DQGSUR DGHQLQHGLQXFOHRWLGH RIFHOOXODUDGHQRVLQH WKHÀQDO VWDJHV RI Y YHVLFDQWPRGHO 0( DO DQG FXWDQ )RU V\VWHPLF YDSRUH[SRVXUHPRG
Decision Tree Ne
$ '71 KDV EHH FDQGLGDWH SUHWUHDWP WKURXJKLQYLWURDQG WHULVWLFVRIWKHFRPS
In Vitro Screening
$VFRPSRXQGV D WKH\ DUH DVVLJQHG WR WKH\ DUH HYDOXDWHG F\WRWR[LFLW\LQKXPD RI+'GHSOHWLRQRIP SURWHRO\VLV5HVXOWV FRPSRXQGVLQWRWKH
In Vivo Screening
&RPSRXQGVSDVV FDEOH WR LQ YLWUR VF 0(90IRUHGHPDD GHUPDOQHFURVLVHYD
SRVXUHWR+'6WXGLHVRILQGLYLGXDOWR[LFHYHQWVVXFKDVDON\ FURPROHFXOHV IRUPDWLRQRI'1$VWUDQGEUHDNV DFWLYDWLRQRI O\PHUDVH3$53RU3$'353GLVUXSWLRQRIFDOFLXPUHJXODWLRQ DQGWLVVXHLQÁDPPDWLRQKDYHWRJHWKHUOHGWRWKHIRUPXODWLRQ KHUDSHXWLFLQWHUYHQWLRQ6PLWKHWDO7KHSURSRVHG HJLHVDUHLQWUDFHOOXODUVFDYHQJHUV'1$FHOOF\FOHPRGXODWRUV OFLXP PRGXODWRUV SURWHDVH LQKLELWRUV DQG DQWLLQÁDPPDWRU\
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
EXPERIMENTAL DESIGN
twork (DTN)
Q GHYLVHG WR RXWOLQH WKH VHOHFWLRQ SURFHVV XVHG WR HYDOXDWH HQW RU WUHDWPHQW FRPSRXQGV 7KLV '71 FRQVLVWV RI SDWKZD\V LQYLYRFRPSRXQGVFUHHQLQJPRGXOHVEDVHGRQNQRZQFKDUDF RXQGVEHLQJHYDOXDWHG
Modules
UH SODFHG LQ WKHGUXJ DVVHVVPHQW FRPSRXQG WUDFNLQJ V\VWHP VSHFLÀF IXQFWLRQDO FDWHJRULHV%DVHG RQ WKHLU FDWHJRUL]DWLRQ WKURXJK D VHULHV RI DVVD\V VXFK DV DTXHRXV VROXELOLW\ GLUHFW QO\PSKRF\WHV3%/SURWHFWLRQRI3%/DJDLQVWWKHF\WRWR[LFLW\ HWDEROLFIDFWRUV1$'RU$73DQGLQKLELWLRQRI+'LQGXFHG
IURPWKHVHDVVD\VDUHXVHGWRSULRULWL]HPRYHPHQWRIFDQGLGDWH LQYLYRVFUHHQLQJPRGXOHV
Modules
LQJWKHLQYLWURPRGXOHVRUFRPSRXQGVIURPFODVVHVQRWDSSOL UHHQLQJ LH DQWLLQÁDPPDWRU\ FRPSRXQGV DUH WHVWHG LQ WKH QGKLVWRSDWKRORJLFLHHSLGHUPDO²GHUPDOVHSDUDWLRQDQGHSL OXDWLRQ2WKHULQYLYRDVVD\VDYDLODEOHIRUDGGLWLRQDOWHVWLQJDV
UHTXLUHG LQFOXGH FXW GRPHVWLFVZLQHDQGF 7KHVHPRGXOHV XVXD QHZPRGXOHVDUHEHL
Basic Research
$IWHULWVLQWURGXF PRVWRIWKHUHVHDUFK ORJLFDO VHTXHODH RI UHOHYDQWDQLPDOPRGH WKHELRFKHPLFDOHIIH RILGHQWLI\LQJWKHUDSH LQURDGVIRURXUXQGH ZHUHIXWLOH,QWKH DQGUHSDLUF\WRWR[LF
$URXQGWKH LQWHUYHQWLRQ VWUDWHJLH DQG7HFKQRORJ\2EM $JHQWV7KLV672SUH DQGSDWKRSK\VLRORJLF JLHVIRUWKH+'LQMXU\ LQDQDQLPDOPRGHO
7KHÀUVW WHFKQLF RIWKH86$05,&' PHGLFDO UHVHDUFK SU DEOH WR FRQVWUXFW D GRFXPHQWHGLQFHOOV SUHVHQWHGDWQXPHUR LQFOXGLQJWKHWK$ ÀQGLQJVRIWKLVSURJ +'UHVHDUFK6PLWK
7KHVHFRQGSDUWR SURWHFWLRQDJDLQVWWK IRUWKHSDWKRORJ\VF DQLVPWKDWFRXOGVHUY 7KHVHZHUHSUHVHQWH DUHSUHVHQWHGLQ7DEO EHHQVKRZQWREHHI
7KH WHFKQL FDQGLGDWH FRXQWHUPH KDLUOHVV JXLQHD SLJV 0(90&DVLOODVHW
DQHRXV +' YDSRU H[SRVXUH LQ WKH KDLUOHVV JXLQHD SLJ RU WKH XWDQHRXV+'YDSRUDQGOLTXLGH[SRVXUHVLQWKHKDLUOHVVPRXVH OO\ HPSOR\ WRSLFDO WUHDWPHQW ZLWK FDQGLGDWH FRPSRXQGV EXW QJGHVLJQHGIRUV\VWHPLFWUHDWPHQWUHJLPHV
RESULTS AND DISCUSSION
WLRQRQWRWKHEDWWOHÀHOGLQ:RUOG:DU,DQGWKURXJKWKHV HIIRUWVGLUHFWHGWRZDUG+'IRFXVHGRQGHÀQLQJWKHKLVWRSDWKR H[SRVXUH LQ KXPDQV $WWHPSWV ZHUH DOVR PDGH WR HVWDEOLVK OV\VWHPV%HJLQQLQJLQWKHVUHVHDUFKWXUQHGPRUHWRZDUG FWVRI+'DQGHPSLULFDOVWXGLHVZHUHFRQGXFWHGZLWKWKHDLP XWLFPRGDOLWLHV:KLOHWKHELRFKHPLFDOVWXGLHVOHGWRVLJQLÀFDQW UVWDQGLQJRIWKHWR[LFPHFKDQLVPVWKHWKHUDSHXWLFDSSURDFKHV VDQGV+'UHVHDUFKIRFXVHGPRVWO\RQ'1$GDPDJH PHFKDQLVPVDQGPXWDJHQHVLV 86$UP\GHFLGHGWRIRFXVLWVHIIRUWVIRUGHYHORSLQJPHGLFDO V IRU+' LQMXU\ WKURXJK WKH IRUPXODWLRQRIDQ$UP\6FLHQFH HFWLYH672WLWOHG0HGLFDO&RXQWHUPHDVXUHVDJDLQVW9HVLFDQW VHQWHGWKUHHWHFKQLFDOPLOHVWRQHVE\GHÀQHWHFKQRORJLFDO DOGDWDEDVHVDQGHVWDEOLVKSKDUPDFRORJLFDOLQWHUYHQWLRQVWUDWH E\VKRZHIÀFDF\RIDFDQGLGDWHPHGLFDOFRXQWHUPHDVXUH DQGE\SUHSDUHDPLOHVWRQHGUXJGHYHORSPHQWGHFLVLRQ DOPLOHVWRQH IRU ZDVPHW WKURXJK WKH UHVHDUFK HIIRUWV WKHH[WUDPXUDOFRQWUDFWSURJUDPRIWKH86$050&DQGWKH RJUDPV RI RXU DOOLHG QDWLRQV )URP WKLV UHVHDUFK ZHZHUH VFKHPD RI WKH PDMRU HYHQWV RI WKH SDWKRORJLFDO SURFHVVHV DQGWLVVXHVH[SRVHGWR+')LJXUH7KLVVFKHPDZDV XV'HSDUWPHQWRI'HIHQVHDQGSURIHVVLRQDOVFLHQWLÀFIRUXPV UP\6FLHQFH&RQIHUHQFH6PLWKHWDO7KHUHVHDUFK UDPVHUYHGDVWKHFRUHRID1$72VSRQVRUHGPRQRJUDSKRQ DQG0RO IWKHPLOHVWRQHLHGHÀQHVWUDWHJLHVIRUSKDUPDFRORJLFDO HYHVLFDQWLQMXU\ZDVPHWE\XVLQJWKHLQIRUPDWLRQGHYHORSHG KHPD:HLGHQWLÀHGVL[VSHFLÀFDUHDVRIWKHSDWKRORJLFPHFK HDVSRLQWVRISKDUPDFRORJLFDOLQWHUYHQWLRQLQWRWKH+'LQMXU\ GDORQJZLWKWKHSDWKRORJ\VFKHPDDWQXPHURXVPHHWLQJVDQG HDORQJZLWKSURWRW\SLFFRPSRXQGVLQHDFKDUHDWKDWKDYH
ÀFDFLRXVDJDLQVW+'WR[LFLW\LQYDULRXVPRGHOV\VWHPV FDO PLOHVWRQH FDOOHG IRU WKH GHPRQVWUDWLRQ RI HIÀFDF\ E\ D DVXUH LQ DQ DQLPDOPRGHO7KLVZDV ÀUVWPHW E\ UHVHDUFK LQ E\<RXULFN HW DO DQG VXEVHTXHQWO\ FRQÀUPHG LQ WKH DO6PLWKHWDO
Candidate Compo
,QÀVFDO\HDU WHFKQRORJ\REMHFWLYH LQWDFW D QHZ PHWUL LGHQWLI\LQJ FRPSRXQ ZHZHUHUHTXLUHGWR
2YHUFDQGLG WKURXJKWKHDQWLYHVL WRSURYLGHVLJQLÀFDQ YLYR2IWKHVHFR
und Screening
WKHSURJUDPZDVFRQYHUWHGIURPDQ$UP\672WRDGHIHQVH '72&%DQGZKLOH WKH WHFKQLFDOPLOHVWRQHV UHPDLQHG F ZDV LPSRVHG RQ WKH GUXJ GHYHORSPHQW HIIRUW 5DWKHU WKDQ GV WKDW MXVW VLJQLÀFDQWO\ UHGXFHG RXU SDWKRORJLFDO HQGSRLQWV
Proposed Mechanism of HD Action
DWWDLQDWOHDVWUHGXFWLRQRILQGLFDWRUVRIPRUELGLW\ DWHSURSK\ODFWLFRUWKHUDSHXWLFFRPSRXQGVKDYHEHHQHYDOXDWHG FDQW'716L[W\WZRFRPSRXQGVKDYHGHPRQVWUDWHGDQDELOLW\ WPRGXODWLRQRIHGHPDDQGRUKLVWRSDWKRORJ\FDXVHGE\+'LQ PSRXQGVKDYHGHPRQVWUDWHGDWOHDVWSURWHFWLRQDJDLQVW
WKHSDWKRORJLFDOLQGL FDQGLGDWHVIDOOLQWRI 6PLWKDQG0RO DORU3$53
:LWKWKHVHFRPS WRFRQFHSWGHYHORSP DQGZRUNKDVEHHQLQ H[SORUDWLRQWRZDUGD WLPHSHULRG
Future
+DYLQJHVWDEOLVK FRXQWHUPHDVXUHDJDL GLGDWH FRPSRXQGV I
FDWRUVRIPXVWDUGLQMXU\7DEOH$OORIWKHVHVXFFHVVIXO RXURIRXUVL[RULJLQDOSURSRVHGVWUDWHJLHVDQWLLQÁDPPDWRULHV DQWLSURWHDVHV 6PLWKHWDO VFDYHQJHUV <RXULFNHW LQKLELWRUV6PLWKHWDO RXQGVDVSURRIRIFRQFHSWZHUHFHLYHGDSSURYDOIRUWUDQVLWLRQ HQWLQ1RYHPEHU$QHZ'72&%KDVEHHQDSSURYHG LWLDWHGWRGULYHWKHGUXJGHYHORSPHQWSURFHVVWKURXJKFRQFHSW WUDQVLWLRQWRDGYDQFHGGHYHORSPHQWLQWKHÀVFDO\HDU
HGSURRIRIFRQFHSWIRUWKHSRWHQWLDOGHYHORSPHQWRIDPHGLFDO QVWYHVLFDQWDJHQWVZHZLOOPRYHWKHPRVWVXFFHVVIXOFDQ URP EDVLF UHVHDUFK LQWR WKH FRQFHSW H[SORUDWLRQ SKDVH RI WKH
GUXJGHYHORSPHQWS ZHZLOOSUHVHQWWRWKH FDQGLGDWHURXWHRID GUXJGHYHORSPHQWZ
7KLVUHVHDUFKKD 0HGLFDO&RXQWHUPHD PHWHYHU\PLOHVWRQH WKHUDSHXWLF VWUDWHJLH HIÀFDF\ LQ DQ DQLP FDSDEOHRISURWHFWLQJ WRPRYH IURP WKH UH H[SORUDWLRQSKDVHRI DFDGHPLFLQGXVWULDO RSPHQW RI D ÀHOGHG +'·V LQWURGXFWLRQ R SRWHQWLDOWRSURWHFWR FRORJLFDOWKHUDS\
URFHVV7KURXJKDGRZQVHOHFWLRQSURFHVVFXUUHQWO\XQGHUZD\ 86$UP\0HGLFDO0DWHULHO'HYHORSPHQW$FWLYLW\WKHRSWLPDO GPLQLVWUDWLRQDQGWLPLQJRIGRVDJHIRUWUDQVLWLRQWRDGYDQFHG LWKLQ\HDUV
CONCLUSIONS
VEHHQGLUHFWHGDWPHHWLQJWKHPHGLFDOFKHPLFDOGHIHQVH'72 VXUHVDJDLQVW9HVLFDQW$JHQWV%DVHGRQUHVXOWVWRGDWHZHKDYH RIWKH'72LH´ WRGHYHORSDWHFKQRORJLFDOGDWDEDVHDQGGHÀQH V WKDW SURWHFW DJDLQVW WKH YHVLFDQW LQMXU\µ DQG ´GHPRQVWUDWH DO PRGHOµ +DYLQJ LGHQWLÀHG DW OHDVW FRPSRXQGV WKDW DUH DJDLQVWWKHLQYLYRSDWKRORJ\RI+'ZHQRZKDYHWKHPHDQV VHDUFKSKDVHRISKDUPDFHXWLFDO LQYHVWLJDWLRQ LQWR WKHFRQFHSW GUXJGHYHORSPHQW7KLVZRUN WKHFRPELQHGHIIRUWVRIDUP\ DQGFRQWUDFWHGUHVHDUFKODERUDWRULHVKDVVHWWKHVWDJHIRUGHYHO PHGLFDO FRXQWHUPHDVXUH DJDLQVW+')RU WKH ÀUVW WLPH VLQFH QWR WKH EDWWOHÀHOGPRUH WKDQ \HDUV DJRZH KDYH WKH WUXH XUZDUÀJKWHUVDJDLQVWWKLVLQVLGLRXVZHDSRQWKURXJKSKDUPD
REFERENCES
