Current Drug Discovery Technologies



Send Orders for Reprints to [email protected] 

Current Drug Discovery Technologies, , 13, 

5(6($5&+$57,&/( ISSN: 1570-1638 eISSN: 1875-6220

Drug Discovery Technologies

Current

4XDQWLWDWLYH 6WUXFWXUH&\WRWR[LF $FWLYLW\ 5HODWLRQVKLS  %HQ]R\OR[\ XUHDDQG,WV'HULYDWLYH 6XNR+DUGMRQR 6LVZDQGRQR6LVZRGLKDUGMR3XUZDQWR3UDPRQRDQG:LQ'DUPDQWR 1 2

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Universitas Airlangga, Surabaya, Indonesia; Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia

$57,&/(+,6725< 5HFHLYHG)HEUXDU\ 5HYLVHG0D\ $FFHSWHG0D\  DOI: 10.2174/15701638136661605251123 27

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¶V PHWKRG E\ WKH DGGLWLRQ RI EHQ]R\O JURXS DQG LWV KRPRORJV UHVXOWHG LQ WKH LQFUHDVH RI OLSRSKLOLF HOHFWURQLF DQG VWHULF SURSHUWLHV DQG F\WRWR[LF DFWLYLW\ 6\QWKHVL]HG FRPSRXQGVZHUH EHQ]R\OR[\ XUHDDQGLWVGHULYDWLYHV6WUXFWXUHFKDUDFWHUL]DWLRQZDVREWDLQHGE\ WKHVSHFWUXPRI89,5+105&105DQG0DVV6SHFWURPHWHU$QWLFDQFHUDFWLYLW\ZDVFDUULHG RXWXVLQJ077PHWKRGRQ+H/DFHOOV7KH4XDQWLWDWLYH6WUXFWXUH&\WRWR[LF$FWLYLW\5HODWLRQVKLSV RI  EHQ]R\OR[\ XUHD FRPSRXQG DQG LWV GHULYDWLYHV ZDV FDOFXODWHG XVLQJ 6366 7KH FKHPLFDO VWUXFWXUHZDVGHVFULEHGQDPHO\&ORJ3ʌı56&05DQG(VZKLOHWKHF\WRWR[LFDFWLYLW\ZDV LQGLFDWHG E\ ORJ   ,&  7KH UHVXOWV VKRZ WKDW WKH EHVW HTXDWLRQ RI 4XDQWLWDWLYH 6WUXFWXUH &\WRWR[LF$FWLYLW\5HODWLRQVKLSV 46$5 RI EHQ]R\OR[\ XUHDFRPSRXQGDQGLWVGHULYDWLYHVLV /RJ,&   ı±  (V±  

.H\ZRUGV3K\VLFRFKHPLFDOSDUDPHWHUVF\WRWR[LFDFWLYLW\ EHQ]R\OR[\ XUHD46$5 ,1752'8&7,21

$GGUHVV FRUUHVSRQGHQFH WR WKLV DXWKRU DW WKH 3KDUPDFHXWLFDO &KHPLVWU\ 'HSDUWPHQW )DFXOW\ RI 3KDUPDF\ 8QLYHUVLWDV $LUODQJJD 6XUDED\D,QGRQHVLD(PDLOVXNRKDUGMRQR#\DKRRFRP

FRQILUPWKHVWUXFWXUHDQGWRGRELRORJLFDODFWLYLW\ WHVW 7KH ODVW VWHS LV WR IRUPXODWH WKH TXDQWLWDWLYH UHODWLRQVKLS EHWZHHQ VWUXFWXUH SK\VLFRFKHPLFDO SURSHUWLHVDQGELRORJLFDODFWLYLW\46$5E\XVLQJ VWDWLVWLFDOUHJUHVVLRQDQDO\VLV>@,WLVDVWDWLVWLFDO PRGHOWKDWUHODWHVDVHWRIVWUXFWXUDOGHVFULSWRUV RI DFKHPLFDOFRPSRXQGWRLWVELRORJLFDODFWLYLW\.7R SURYLGH VRPH JXLGH LW LV ZLGHO\ DFFHSWHG WKDW EHWZHHQ ILYH DQG WHQ FRPSRXQGV DUH UHTXLUHG IRU HYHU\GHVFULSWRULQD46$5>@6RPHUHVHDUFKHUVXVH 46$5 DV UHVHDUFK PRGHOV %KDUDWH 63 et al VWXGLHG WKHDQWLOHLVKPDQLDODFWLYLW\RIVHYHUDOVWUXFWXUDOO\ VLPLODU QDWXUDOO\ RFFXUULQJ JOREDO V IURP 0\UWDFHDHIDPLO\ZKLFKKDYHDOVREHHQSUHGLFWHG XVLQJ GHYHORSHG 46$5 PRGHO >@ 5ROOL ( et al VWXGLHG 1SKHQ\O1¶EHQ]RWKLD]RO\OXUHD 3%8  GHULYDWLYHVDQGREVHUYHGWKHDDGYHQWLWLRXVURRWLQJ



 !"#"$%&'#()(

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

1875-6220

Current Drug Discovery Technologies, , Vol. 13, No. 2

DGMXYDQW DFWLYLW\ ZDV VWULFWO\ GHSHQGHQW RQ WKHLU FKHPLFDO VWUXFWXUH >@ E@ LQGROH GHULYDWLYHV E\ 46$5 >@ 6KDOLQL 6LQJK VWXGLHG FRPSXWDWLRQDO GHVLJQ DQG FKHPRPHWULF 46$5 PRGHOLQJ RI 3ODVPRGLXP IDOFLSDUXPFDUERQLFDQK\GUDVHLQKLELWRUV>@ 7RSOLVV   SURSRVHG D VFKHPH RU DQ RSHUDWLRQDOGLDJUDP WR V\QWKHVL]H DQDORJV LQ GUXJ GHVLJQ 7KLV GLDJUDP LV EDVHG RQ WKH EDVLF DVVXPSWLRQ RI +lQVFK¶V PHWKRG WKDW D SDUWLFXODU VXEVWLWXHQW PD\ DOWHU WKH UHODWLYH DFWLYLW\ WR WKH PRWKHU FRPSRXQG EDVHG RQ FKDQJHV LQ WKH K\GURSKRELF HOHFWURQLF HIIHFWV DQG VWHULF >@ $ VXEVWLWXWLRQ RQ WKH JXLGLQJ FRPSRXQGV DOWHUV WKH SK\VLFRFKHPLFDO SURSHUWLHV ZKLFK LQFOXGH OLSRSKLOLF HOHFWURQLF DQG VWHULF SURSHUWLHV >@ 8QWLO QRZ UHVHDUFKHUV DUH VWLOO XVLQJ WKH 7RSOLVV¶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

Hardjono et al.

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

Quantitative Structure-Cytotoxic Activity Relationship

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ʌ HOHFWURQLF SDUDPHWHUV ı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

Current Drug Discovery Technologies, , Vol. 13, No. 2 

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ʌı 56 &05 DQG (V 3K\VLFRFKHPLFDO SDUDPHWHUV WKHRUHWLFDOO\REWDLQHGIURPWH[WERRNVRU&KHP%LR 'UDZ8OWUDH[FHSW56REWDLQHGIURPWKHLQVLOLFR WHVW &\WRWR[LF DFWLYLW\ ZDV LQGLFDWHG E\ /RJ ,&  5(68/76$1'',6&866,216 In Silico7HVW )URPWKHUHVXOWVRILQVLOLFRWHVWVIRUDOOVXEVWDQFHV RQ (8' WKH QXPEHU RI K\GURJHQ ERQGV DQG WKH YDOXH5HUDQN6FRUHKDYHEHHQREVHUYHGDVVKRZQLQ 7DEOH$QH[DPSOHRIGRFNLQJWKHFRPSRXQG  WEXW\OEHQ]R\OR[\ XUHD ZLWK (8' FDQ EH VHHQ LQ )LJVDQG 6\QWKHVLV  WHQ  FRPSRXQGV LQFOXGLQJ  EHQ]R\OR[\ XUHD DQG LWV GHULYDWLYHV KDYH EHHQ V\QWKHVL]HG E\ QXFOHRSKLOLF VXEVWLWXWLRQ RI

Current Drug Discovery Technologies, , Vol. 13, No. 2 7DEOH

Hardjono et al.

$PLQRDFLGVDUHLQYROYHGLQK\GURJHQERQGLQJDQG5HUDQN6FRUHRQLQWHUDFWLRQ EHQ]RLORNVL XUHDDQGLWVGHULYDWLYHV ZLWK(8'

1R

5 

5

&@ >@ >@

>@ >@

>@

>@ >@ >@ >@

>@

6LVZDQGRQR GDQ %DPEDQJ 6RHNDUGMR Kimia Medisinal $LUODQJJD 8QLYHUVLW\3UHVV 6LVZDQGRQR 0RGLILNDVL 6WUXNWXU GDQ +XEXQJDQ 6WUXNWXU $NWLYLWDV 6HQ\DZDVHQ\DZD %DUX 7XUXQDQ %HQ]R\OXUHD $LUODQJJD 8QLYHUVLW\ 'LVVHUWDWLRQ6XUDED\D 2NVHO & :DQJ ;= 4XDQWLWDWLYH 6WUXFWXUHǦ$FWLYLW\ 5HODWLRQVKLS 46$5  PRGHOV´ 8QLYHUVLW\ RI /HHGV KWWSTXDOLW\QDQRHXXSORDGV6FKRRO7UDLQLQJ0DWHULDOV46$5V /HFWXUHB&H\GD2NVHOSGI %KDUDWH6%6LQJK,34XDQWLWDWLYHVWUXFWXUH±DFWLYLW\UHODWLRQVKLSVWXG\ RI SKORURJOXFLQROWHUSHQH DGGXFWV DV DQWLOHLVKPDQLDO DJHQWV %LRRUJ 0HG&KHP/HWWHUV± 5ROOL ( ,QFHUWL 0 %UXQRQL ) 9LFLQL 3 5LFFL $ 6WUXFWXUH±DFWLYLW\ UHODWLRQVKLSV RI 1SKHQ\O1¶EHQ]RWKLD]RO\OXUHD V\QWKHWLF GHULYDWLYHV&\WRNLQLQOLNHDFWLYLW\DQGGYHQWLWLRXVURRWLQJHQKDQFHPHQW 3K\WRFKHPLVWU\± E@LQGROHV(XU-0HG&KHP 6LQJK 6 &RPSXWDWLRQDO GHVLJQ DQG FKHPRPHWULF 46$5 PRGHOLQJ RI 3ODVPRGLXP IDOFLSDUXP FDUERQLF DQK\GUDVH LQKLELWRUV %LRRUJ 0HG &KHP/HWWHUV± 7RSOLVV-*8WLOL]DWLRQRI2SHUDWLRQDO6FKHPHVIRU$QDORJ6\QWKHVLVLQ 'UXJ'HVLJQ-0HG&KHP   .RURONRYDV$(VVHQWLDOVRI0HGLFLQDO&KHPLVWU\HQGHG1HZ@

>@ >@

>@ >@ >@ >@ >@

>@ >@ >@ >@ >@ >@ >@ >@ >@

>@ >@ >@

=DFKLIPDQ - (QDP 3 3HQGXGXN 5, 0HQGHULWD . 'HSDUWHPHQ .HVHKDWDQ,QGRQHVLDZZZGHSNHVJRLG'HFHPEHU 5LVNHVGDV +HDOWK 5HVHDUFK  WKH $JHQF\ IRU +HDOWK 5HVHDUFK DQG 'HYHORSPHQW 5HVHDUFK RI WKH 0LQLVWU\ RI +HDOWK 5, KWWSZZZGHSNHVJRLGUHVRXUFHV GRZQORDG JHQHUDO +DVLO5LVNHVGDVSGI  .KD\DW $6 *XLPDUmHV $& &DUGRVR 3& et al 0XWDJHQLFLW\ RI +\GUR[\XUHD LQ /\PSKRF\WHV IURP 3DWLHQWV ZLWK 6LFNOH &HOO 'LVHDVH *HQHW0RO%LRO   &KDEQHU%$5\DQ'33D]$UH]/*DUFLD&DUERQHUR5RFLR&DODEUHVL 3DXO $QWLQHRSODVWLF $JHQW ,Q *RRGPDQ *LOPDQ¶V 7KH 3KDUPDFRORJLFDO%DVLVRI7KHUDSHXWLFV0F*UDZ+LOO1HZ

Quantitative Structure-Cytotoxic Activity Relationship 1-(Benzoyloxy)urea and Its Derivative.

Drug development is originally carried out on a trial and error basis and it is cost-prohibitive. To minimize the trial and error risks, drug design i...
3MB Sizes 2 Downloads 6 Views