Organophosphorus compounds (OP) nerve agents are among the most toxic chemical substances known. Their toxicity is due to their ability to bind to acetylcholinesterase. Currently, some enzymes, such as phosphotriesterase, human serum paraoxonase 1 and diisopropyl fluorophosphatase, capable of degrading OP, have been characterized. Regarding the importance of bioremediation methods for detoxication of OP, this work aims to study the interaction modes between the human human deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and Sarin and VX, considering their Rp and Sp enantiomers, to evaluate the asymmetric catalysis of those compounds. In previous work, this enzyme has shown good potential to degrade phosphotriesters, and based on this characteristic, we have applied the human dUTPase to the OP degradation. Molecular docking, chemometrics and mixed quantum and molecular mechanics calculations have been employed, showing a good interaction between dUTPase and OP. Two possible reaction mechanisms were tested, and according to our theoretical results, the catalytic degradation of OP by dUTPase can take place via both mechanisms, beyond being stereoselective, that is, dUTPase cleaves one enantiomer preferentially in relation to other. Chemometric techniques provided excellent assistance for performing this theoretical investigation. The dUTPase study shows importance by the fact of it being a human enzyme. Communicated by Ramaswamy H. Sarma.

b Institute of Exact and Biological Sciences Federal University of Ouro Preto University Campus Ouro Preto Brazil

Laboratory of Molecular Modeling Chemistry Department Federal University of Lavras Lavras Brazil

Laboratory of Molecular Modeling Chemistry Department Federal University of Lavras Lavras Brazil c Center for Basic and Applied research University Hradec Kralove Hradec Kralove Czech Republic

000      

00000naa a2200000 a 4500

001      

bmc20023968

003      

CZ-PrNML

005      

20201214131906.0

007      

ta

008      

201125s2019 xxk f 000 0|eng||

009      

AR

024    7_

$a 10.1080/07391102.2018.1478751 $2 doi

035    __

$a (PubMed)30044197

040    __

$a ABA008 $b cze $d ABA008 $e AACR2

041    0_

$a eng

044    __

$a xxk

100    1_

$a de Castro, Alexandre A $u a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , Brazil.

245    10

$a Asymmetric biodegradation of the nerve agents Sarin and VX by human dUTPase: chemometrics, molecular docking and hybrid QM/MM calculations / $c AA. de Castro, FV. Soares, AF. Pereira, TC. Silva, DR. Silva, DT. Mancini, MS. Caetano, EFF. da Cunha, TC. Ramalho,

520    9_

$a Organophosphorus compounds (OP) nerve agents are among the most toxic chemical substances known. Their toxicity is due to their ability to bind to acetylcholinesterase. Currently, some enzymes, such as phosphotriesterase, human serum paraoxonase 1 and diisopropyl fluorophosphatase, capable of degrading OP, have been characterized. Regarding the importance of bioremediation methods for detoxication of OP, this work aims to study the interaction modes between the human human deoxyuridine triphosphate nucleotidohydrolase (dUTPase) and Sarin and VX, considering their Rp and Sp enantiomers, to evaluate the asymmetric catalysis of those compounds. In previous work, this enzyme has shown good potential to degrade phosphotriesters, and based on this characteristic, we have applied the human dUTPase to the OP degradation. Molecular docking, chemometrics and mixed quantum and molecular mechanics calculations have been employed, showing a good interaction between dUTPase and OP. Two possible reaction mechanisms were tested, and according to our theoretical results, the catalytic degradation of OP by dUTPase can take place via both mechanisms, beyond being stereoselective, that is, dUTPase cleaves one enantiomer preferentially in relation to other. Chemometric techniques provided excellent assistance for performing this theoretical investigation. The dUTPase study shows importance by the fact of it being a human enzyme. Communicated by Ramaswamy H. Sarma.

650    _2

$a biodegradace $7 D001673

650    _2

$a katalytická doména $7 D020134

650    _2

$a lidé $7 D006801

650    _2

$a vodíková vazba $7 D006860

650    12

$a simulace molekulového dockingu $7 D062105

650    _2

$a nervová bojová látka $x chemie $x metabolismus $7 D000067397

650    _2

$a organofosforové sloučeniny $x chemie $x metabolismus $7 D009943

650    _2

$a organothiofosforové sloučeniny $x chemie $x metabolismus $7 D009946

650    _2

$a analýza hlavních komponent $7 D025341

650    _2

$a pyrofosfatasy $x metabolismus $7 D011755

650    12

$a kvantová teorie $7 D011789

650    _2

$a sarin $x chemie $x metabolismus $7 D012524

655    _2

$a časopisecké články $7 D016428

700    1_

$a Soares, Flávia Villela $u a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , Brazil.

700    1_

$a Pereira, Ander Francisco $u a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , Brazil.

700    1_

$a Silva, Telles Cardoso $u a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , Brazil.

700    1_

$a Silva, Daniela Rodrigues $u a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , Brazil.

700    1_

$a Mancini, Daiana Teixeira $u a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , Brazil.

700    1_

$a Caetano, Melissa Soares $u b Institute of Exact and Biological Sciences, Federal University of Ouro Preto, University Campus , Ouro Preto , Brazil.

700    1_

$a da Cunha, Elaine F F $u a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , Brazil.

700    1_

$a Ramalho, Teodorico C $u a Laboratory of Molecular Modeling, Chemistry Department , Federal University of Lavras , Lavras , Brazil. c Center for Basic and Applied research, University Hradec Kralove , Hradec Kralove , Czech Republic.

773    0_

$w MED00002554 $t Journal of biomolecular structure & dynamics $x 1538-0254 $g Roč. 37, č. 8 (2019), s. 2154-2164

856    41

$u https://pubmed.ncbi.nlm.nih.gov/30044197 $y Pubmed

910    __

$a ABA008 $b sig $c sign $y a $z 0

990    __

$a 20201125 $b ABA008

991    __

$a 20201214131906 $b ABA008

999    __

$a ok $b bmc $g 1596287 $s 1114644

BAS    __

$a 3

BAS    __

$a PreBMC

BMC    __

$a 2019 $b 37 $c 8 $d 2154-2164 $e 20190109 $i 1538-0254 $m Journal of biomolecular structure & dynamics $n J Biomol Struct Dyn $x MED00002554

LZP    __

$a Pubmed-20201125