Towards new computational tools for predicting toxicity

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(1)Towards new computational tools for predicting toxicity.

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(3) Linnaeus University Dissertations No 243/2016. T OWARDS NEW COMPUTATIONAL TOOLS FOR PREDICTING TOXICITY. S WAPNIL C HAVAN. LINNAEUS UNIVERSITY PRESS.

(4) Towards new computational tools for predicting toxicity Doctoral dissertation, Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden, 2016 ISBN: 978-91-88357-04-5 Published by: Linnaeus University Press, 351 95 Växjö, Sweden Printed by: Elanders Sverige AB, 2016.

(5) Abstract Chavan, Swapnil (2016). Towards new computational tools for predicting toxicity, Linnaeus University Dissertation No 243/2016, ISBN: 978-91-88357-04-5. Written in English. The toxicological screening of the numerous chemicals that we are exposed to requires significant cost and the use of animals. Accordingly, more efficient methods for the evaluation of toxicity are required to reduce cost and the number of animals used. Computational strategies have the potential to reduce both the cost and the use of animal testing in toxicity screening. The ultimate goal of this thesis is to develop computational models for the prediction of toxicological endpoints that can serve as an alternative to animal testing. In Paper I, an attempt was made to construct a global quantitative structure-activity relationship (QSAR) model for the acute toxicity endpoint (LD50 values) using the Munro database that represents a broad chemical landscape. Such a model could be used for acute toxicity screening of chemicals of diverse structures. Paper II focuses on the use of acute toxicity data to support the prediction of chronic toxicity. The results of this study suggest that for related chemicals having acute toxicities within a similar range, their lowest observed effect levels (LOELs) can be used in read-across strategies to fill gaps in chronic toxicity data. In Paper III a k-nearest neighbor (kNN) classification model was developed to predict human ether-a-go-go related gene (hERG)-derived toxicity. The results suggest that the model has potential for use in identifying compounds with hERG-liabilities, e.g. in drug development. Keywords Acute toxicity, chronic toxicity, hERG, k-NN, LD50, LOEL, Munro database, QSAR, read-across, toxicity.

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(81) ;@JGFA; =>>=;LK 9J= MKM9DDQ KLM<A=< >GJ 9 KA?FA>A;9FL HGJLAGF G> the organism’s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“lock and key” mechanismAFO@A;@9J=;=HLGJ @9K9;GEHD=E=FL9JQ:AF<AF?KAL=>GJ9<JM?!A?MJ= $>9<JM?@9KL@= ;GJJ=;LK@9H=LG>ALAFL@=J=;=HLGJ:AF<AF?KAL=L@=F9C=Q<JM?;9FGH=F9 DG;CJ=;=HLGJ . .

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(87) >>=;LAN=GF;=FLJ9LAGF

(88) . .LJM;LMJ= 9;LANALQJ=D9LAGFK@AHK /@=:AGDG?A;9D=>>=;LAK?GN=JF=<:QL@=KLJM;LMJ=G>9DA?9F< /@=J=D9LAGFK@AH :=LO==F L@= KLJM;LMJ= G> L@= DA?9F<9F< L@= :AGDG?A;9D 9;LANALQ AK L=JE=< 9K9 KLJM;LMJ= 9;LANALQJ=D9LAGFK@AH.- /@=HJ=K=F;=G>C=QKLJM;LMJ9D=D=E=FLK. .

(89) KM;@ 9K 9 H9JLA;MD9J >MF;LAGF9D ?JGMH >J9?E=FL GJ KM: KLJM;LMJ= AF 9 DA?9F< G>L=FJ=KMDLKAF9;=JL9AFN9JA9LAGFAFALK:AGDG?A;9D9;LANALQ /@=9F9DQKAKG>L@= .- G> 9 D=9< ;GEHGMF< 9F< ALK 9F9DG?K E9Q := MK=< LG <=L=JEAF= L@= KA?FA>A;9F;= G> H9JLK G> L@= KLJM;LMJ= G> L@= D=9< ;GEHGMF< L@9L J=KMDL AF AF;J=9K=<:AGDG?A;9D9;LANALQ9F<J=<M;=<MFO9FL=<KA<==>>=;LK /@=.-;9F :=MK=<LG<=N=DGH9F=O<JM?OAL@AEHJGN=<9;LANALQ9F<D=KKKA<==>>=;LK .-K 9J= MKM9DDQ AFN=KLA?9L=< :Q ;J=9LAF? KDA?@L EG<A>A;9LAGFK LG L@= D=9< ;GEHGMF< LG HJG<M;= F=O 9F9DG?K 9F< E=9KMJAF? L@= AF>DM=F;= G> L@=K= KLJM;LMJ9D ;@9F?=K GF L@=AJ :AGDG?A;9D9;LANALQ /@=K= KLJM;LMJ9D ;@9F?=K ;9F :=:JGM?@L9:GMLAF9FME:=JG>O9QK9KHJ=K=FL=<:=DGO . $FLJG<M;LAGFG>:AG AKGKL=J=K )=O 9F9DG?K LG =PAKLAF? D=9< ;GEHGMF<K ;9F := <=JAN=< :Q J=HD9;AF? 9F =PAKLAF?KLJM;LMJ9DEGA=LQG>9D=9<OAL@9F=OEGA=LQ /@=;@GA;=G>L@=F=O EGA=LQ AK G>L=F :9K=< GF L@= ;GF;=HL G> AKGKL=J=K $KGKL=J=K 9J= L@= ;@=EA;9D ?JGMHKL@9L=P@A:ALKAEAD9JALQAFKGE=G>L@=AJ;@=EA;9DGJH@QKA;9DHJGH=JLA=K 9K9J=KMDLG>@9NAF?L@=K9E=FME:=JG>LGL9DGJN9D=F;==D=;LJGFKO@AD=FGL F=;=KK9JADQ@9NAF?L@=K9E=FME:=JG>9LGEK!A?MJ= $LAK=PH=;L=<L@9L :=AF?KAEAD9JAFKLJM;LMJ=KAKGKL=J=KG>L=F=P@A:ALKAEAD9JH@9JE9;GCAF=LA;9F< H@9JE9;G<QF9EA;HJGH=JLA=K@GO=N=JAKGKL=JA;9F9DG?K<GFGLK@GO9KAEAD9J LQH=G>9;LANALQAF=N=JQ;9K= . !A?MJ= P9EHD=KG>AKGKL=J=KO@=J==9;@JGOJ=HJ=K=FLKAKGKL=JA;?JGMHK . .

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

(91) #9FK;@ =L 9D AF HM:DAK@=< 9 KLM<Q G> L@= AF>DM=F;= G> L@= #9EE=LL ;GFKL9FL 9F< @Q<JGH@G:A;ALQ GF L@= KLJM;LMJ= 9;LANALQ J=D9LAGFK@AH G> HD9FL ?JGOL@J=?MD9LGJK 'G? 9DG?+:DG?+;ı+ …+ k . . 2@=J= ;GF;=FLJ9LAGFL@9LHJG<M;=K:AGDG?A;9D=>>=;L +G;L9FGD O9L=J;G=>>A;A=FL 9:;;G=>>A;A=FLK C4 AFL=J;=HL ı=D=;LJGFA;#9EE=LL;GFKL9FL /@=!J== 2ADKGF9HHJG9;@HJGHGK=<L@9LFGH@QKA;G;@=EA;9DH9J9E=L=JK9J= J=IMAJ=<>GJL@=KLJM;LMJ=9;LANALQJ=D9LAGFK@AHAFKL=9<L@=;GFLJA:MLAGFG>=9;@ KLJM;LMJ9D >=9LMJ= O9K G> AFL=J=KL

(92) /@= KAEHD=KL =IM9LAGF >GJ 9 :AGDG?A;9D J=KHGFK=->GDDGOK . log BR = ∑(substituent contributions) + contribution from base molecule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

(93) .

(94) .

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(99)

(100)

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(102)

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(104) =PL=F<AF? 9F< =D9:GJ9LAF? L@= =PAKLAF? AF>GJE9LAGF KG 9K LG AEHJGN= F=O L=KLAF? KLJ9L=?A=K >GJ HJ=<A;LAF? @ME9F @9R9J<K 9F< 9KK=KKAF? =FNAJGFE=FL9D JAKCK ;@=EA;9D;9L=?GJQAK<=>AF=<9K9?JGMHG>;@=EA;9DKO@GK=LGPA;GDG?A;9DGJ H@QKA;G;@=EA;9D HJGH=JLA=K 9J= DAC=DQ LG := KAEAD9J :=;9MK= G> L@=AJ KLJM;LMJ9D KAEAD9JALQ The ‘similarity’ rationale;9F:=<=K;JA:=<9K;@=EA;9DKL@9L@9N= ¾ 9;GEEGF>MF;LAGF9D?JGMHK= ? =HGPA<=9D<=@Q<==L; ¾ AF;J=E=FL9DGJ<=;J=E=FL9D;@9F?=KAFKLJM;LMJ== ? ;@9AFD=F?L@ ¾ ;GEEGF;@=EA;9D;D9KK=KGJ;GFKLALM=FLK ¾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linear relationship is established between ‘m’ number of 3K 9F< L@= :AGDG?A;9D 9;LANALQ <9L9 4 L@JGM?@ 9 DAF=9J =IM9LAGF .M;@ 9 J=D9LAGFK@AH;9F:==PHJ=KK=<OAL@9EMDLAHD= DAF=9J=IM9LAGF 4:

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(124) N9DM=K >GJ 9DD L@=K= KGJL=< ;@=EA;9DK O=J= K=9J;@=< AF L@= /GPF=L 9F< -/ . O=:K=JN=JK -=;GJ<K OAL@ EGJ= L@9F GF= N9DM= O=J= <AK;9J<=< !AF9DDQ'

(125) N9DM=K>GJ ;@=EA;9DKO=J=J=LJA=N=<>JGEL@=/GPF=L9F<L@= -/ .O=:K=JN=JK . (=L@G<GDG?Q =K;JAHLGJ;9D;MD9LAGFK /OG <AE=FKAGF9D J9?GF EGD=;MD9J <=K;JAHLGJK O=J= MK=< >GJ L@= EG<=D ;GFKLJM;LAGF LGL9DG><=K;JAHLGJKO=J= ;GEHML=<>GJ=9;@G>L@= ;@=EA;9DK MKAF? L@= J9?GF KG>LO9J=

(126) >ADL=JAF? G> L@= <=K;JAHLGJK O9K 9;@A=N=<:Q<AK;9J<AF?<=K;JAHLGJKOAL@GF=GJEGJ=EAKKAF?N9DM=K9KO=DD9K ;GFKL9FL GJ F=9J ;GFKL9FL N9DM=K .M:K=IM=FLDQ L@= <=K;JAHLGJK OAL@ 9 H9AJ ;GJJ=D9LAGFD9J?=J L@9F O=J= =P;DM<=< J=<M;=< HGGD G> L@= <=K;JAHLGJ K=LO9KJ=F<=J=<OAL@

(127) <=K;JAHLGJK =K;JAHLGJ>ADL=JAF?9F<GMLDA=J<=L=;LAGF +JAF;AH9D GEHGF=FL F9DQKAK + O9K =EHDGQ=< LG >ADL=J <=K;JAHLGJK AF GJ<=J LG J=EGN= AJJ=D=N9FL GF=K /@= + KLM<Q O9K H=J>GJE=< GF 9DD ;@=EA;9DK MKAF?

(128) <=K;JAHLGJK /@= <9L9 O9K9MLG K;9D=< :=>GJ= L@= + KLM<Q /=FHJAF;AH9D;GEHGF=FLKO=J=MF<=JL9C=F>GJL@=+KLM<Q /GKGJL L@= J=D=N9FL <=K;JAHLGJK 9 DG9<AF? K;GJ= L@J=K@GD< G>

(129)

(130) O9K MK=< O@A;@ >ADL=J=<

(131) <=K;JAHLGJK /@=K=<=K;JAHLGJKO=J=;GFKA<=J=<>GJ>MJL@=JKLM<A=K 9F<GL@=JAJJ=D=N9FL<=K;JAHLGJKO=J=J=EGN=< $F9<<ALAGF>AN=;@=EA;9DKO=J= A<=FLA>A=< 9K HGL=FLA9D GMLDA=JK AF L@= + K;GJ= HDGL 9F< L@MK L@=Q O=J= =P;DM<=< >JGE >MJL@=J KLM<A=K /@= >AF9D <9L9K=L ;GFKA<=J=< >GJ L@= EG<=D <=N=DGHE=FL;GEHJAK=<G>;@=EA;9DK9DGF?OAL@L@=AJ

(132) <=K;JAHLGJK (G<=D<=N=DGHE=FL D9KKA>A;9LAGFK;@=E= /@=IM9FLAL9LAN=LGPA;GDG?A;9DJ=KHGFK=O9K ;D9KKA>A=<AF9IM9DAL9LAN=;D9KKGF L@= :9KAK G> L@= "DG:9DDQ #9JEGFAR=< .QKL=E /@J== ;D9KK=K O=J= >GJE=< D9KK $ '

(133) ≤ 300 E? C? <9Q @A?@DQ LGPA; D9KK $$

(134)

(135) '

(136) ≤ 2000 E? C? <9Q AFL=JE=<A9L= LGPA; 9F< D9KK $$$ '

(137)

(138)

(139)

(140) E? C? <9Q DGO LGFGF LGPA; .

(141) .

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e have selected the ‘Euclidean’ <AKL9F;=E=L@G<>GJ;9D;MD9LAGFG> L@=<AKL9F;=E9LJA;=K 2@AD=9HHDQAF?L@= C )) 9D?GJAL@E L@= GHLAE9D N9DM= G> C F==<K LG := <=L=JEAF=< 2= @9N= MK=< L@= ;JGKK N9DA<9LAGF E=L@G< >GJ L@AK HMJHGK= K=JA=K G> C N9DM=K O=J= 9KKA?F=<>JGEC LG

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

(144) <=K;JAHLGJK>GJ9DD;@=EA;9DK 9;;GEHDAK@L@= + KLM<Q 9F< LG ;GF<M;L <=K;JAHLGJ K=D=;LAGF :Q "=F=LA; D?GJAL@EK O= @9N= =EHDGQ=< L@= “ga_toolbox” and “pca” Matlab modules developed at (AD9FG @=EGE=LJA;K 9F< ,.- -=K=9J;@ "JGMH 0FAN=JKALQ G> (AD9FG A;G;;9(AD9F$L9DQ (G<=DN9DA<9LAGF /@= (MFJG <9L9K=L ;@=EA;9DK O=J= J9F<GEDQ KHDAL C==HAF?

(145) G> L@= ;@=EA;9DK >JGE =N=JQ ;D9KK AF L@= LJ9AFAF? K=L 9F< L@= J=E9AFAF?

(146) AF L@= L=KLK=L/9:D= /GK=D=;LL@=EGD=;MD9J<=K;JAHLGJK9F<LG;GFKLJM;L L@= ;D9KKA>A;9LAGF EG<=DK L@= LJ9AFAF? K=L O9K MK=< /@= HJ=<A;LAN= HGO=J G> L@AKEG<=DO9K=N9DM9L=<:Q=EHDGQAF?L@=L=KLK=L;@=EA;9DK . .

(147) /9:D= D9KKA>A;9LAGFKG>L@=;@=EA;9DKAFL@=LJ9AFAF?9F<L=KL K=LKHJAGJLGL@=C ))EG<=D;GFKLJM;LAGF . . D9KK . D9KK. D9KK. /GL9D. /J9AFAF?K=L /=KLK=L /GL9D.

(148) . . . . /@= LJ9AFAF? K=L G> ;@=EA;9DK OAL@

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the “classification toolbox” Matlab module <=N=DGH=<9L(AD9FG@=EGE=LJA;K9F<,.-J=K=9J;@?JGMHO9KMK=< . -=KMDLK9F<<AK;MKKAGF "=F=LA;D?GJAL@EGML;GE= /@="KLJ9L=?QO9K9HHDA=<AFGJ<=JLGK=D=;LKA?FA>A;9FL<=K;JAHLGJKO@A;@ D9L=J O=J= MK=< >GJ L@= ;GFKLJM;LAGF G> L@= C )) EG<=D /@= :=KL C )) EG<=D G:L9AF=< >JGE L@= " KLJ9L=?Q ;GFKAKL=< G> <=K;JAHLGJK 9F< O9K 9KKG;A9L=< OAL@ 9 ) -;N G>

(150) 9F< ) ->AL GF L@= LJ9AFAF? K=L G>

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

(152) . . .H+GK8H. . (/. N. . (A. . . . .H(8E. . "/. H.

(153) .

(154) .$

(155) . . F. . .$ . . /.=. . +81.8(-8. . '.8

(156) . . F'. . %8R5. . .(8K. . "/. N.

(157) . %"$. . +81.8A8. <=NA9LAGF>JGEMJ<=FE9LJAP O=A?@L=<:Q$ .L9L= )GJE9DAR=<KH=;LJ9DHGKALAN= KME>JGEMJ<=FE9LJAP O=A?@L=<:QHGD9JAR9:ADALQ (GJ9F9MLG;GJJ=D9LAGFG>D9? O=A?@L=<:QN9F<=J299DK NGDME= (=9F>AJKLAGFAR9LAGFHGL=FLA9D K;9D=<GF 9J:GF9LGE (=9FAF>GJE9LAGFAF<=PGF 9LGEA;;GEHGKALAGF .H=;LJ9DE=9F9:KGDML= <=NA9LAGF>JGEMJ<=FE9LJAP O=A?@L=<:QE9KK "=9JQ9MLG;GJJ=D9LAGFG>D9? O=A?@L=< :QHGD9JAR9:ADALQ - 3 - .LJM;LMJ9D$F>GJE9LAGFGFL=FL AF<=PF=A?@:GJ@GG<KQEE=LJQ G>

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

(159) . + . .

(160) 6. +7. .

(161) 6 .7. . '/!. HGL=FLA9D:AF 3 +3H@GKH@9L=. <=K;JAHLGJK LGE ;=FLJ=< >J9?E=FLK LGE+9AJK. +J=K=F;= 9:K=F;=G>. +9L LGHGDG?A;9D<AKL9F;= +J=K=F;= 9:K=F;=G> .9L LGHGDG?A;9D<AKL9F;= 1=J@99J!AK@:9K= DAF=LGPA;ALQ >JGE('*"+EEGD D. LGE+9AJK (GD=;MD9J HJGH=JLA=K. G> LJ9AFAF? K=L ;@=EA;9DK O=J= ;GJJ=;LDQ HJ=<A;L=< :Q L@= C )) ;D9KKA>A;9LAGF EG<=D The sensitivity describes the model’s ability to correctly A<=FLA>Q L@= ;D9KK >GJ 9 ;@=EA;9D !GJ LJ9AFAF? K=L HJ=<A;LAGF L@= C )) ;D9KKA>A;9LAGF ;JGKK N9DA<9L=< EG<=D <AKHD9Q=< K=FKALANALA=K G>

(162)

(163) 9F<

(164) >GJ ;D9KK=K $ $$ 9F< $$$ J=KH=;LAN=DQ /9:D= . .H=;A>A;ALQ ;@9J9;L=JAR=K L@= 9:ADALQ G> L@= H9JLA;MD9J ;D9KK LG J=B=;L L@= ;@=EA;9DK G> 9DD GL@=J ;D9KK=K /@= C )) ;D9KKA>A;9LAGF ;JGKK N9DA<9L=< EG<=D <AKHD9QK @A?@ KH=;A>A;ALQ N9DM=K >GJ 9DD ;D9KK=K A = L@= EG<=D ;9F HJ=<A;L @A?@DQ LGPA; ;@=EA;9DK;D9KK$OAL@9KH=;A>A;ALQJ9L=G>

(165) 9F<

(166) 9F<

(167) >GJ;D9KK=K $$ 9F< $$$ J=KH=;LAN=DQ !GJ L@= =PL=JF9D N9DA<9LAGF L@= EG<=D @9K K@GOF K=FKALANALA=K G>

(168)

(169) 9F<

(170) >GJ ;D9KK=K $ $$ 9F< $$$ J=KH=;LAN=DQ 9F< ;GJJ=KHGF<AF? KH=;A>A;ALA=K G>

(171)

(172) 9F<

(173) /@= EG<=D ;GJJ=;LDQ A<=FLA>A=<;D9KK=KG>GMLG>;@=EA;9DK>JGEL@==PL=JF9DK=L /9:D= . D9KKA>A;9LAGFH9J9E=L=JKG>L@=C ));D9KKA>A;9LAGFEG<=D ) - . !ALLAF? 1 PL=JF9D.

(174)

(175)

(176) . .=FKALANALQ D9KK $$ $$$. $

(177)

(178)

(179) .

(180)

(181)

(182) .

(183)

(184)

(185) . $. .H=;A>A;ALQ D9KK $$ $$$.

(186)

(187)

(188)

(189) .

(190)

(191)

(192) .

(193)

(194)

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