HQSAR and CoMFA approaches in predicting reactivity of halogenated compounds with hydroxyl radicals

Vrtačnik, Margareta; Voda, Karmen

doi:10.1016/s0045-6535(03)00354-0

Cited by 11 publications

(14 citation statements)

References 18 publications

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“…For example, both HQSAR and CoMFA have been used to predict the half-lives of the hydroxyl radical reaction with substituted aromatic compounds, which are major sources of environmental pollution. These models were in good agreement with the proposed mechanism for the hydroxyl-radical oxidation of halogenated aromatic compounds in the atmosphere [4]. The mutagenicity of a series of nitro compounds to Salmonella typhimurium has been determined using HQSAR [5].…”

Section: Introductionsupporting

confidence: 71%

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Comparative quantitative structure–activity relationship (QSAR) study on acute toxicity of triazole fungicides to zebrafish

Ding

Guo

Song

et al. 2011

Chemistry and Ecology

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We employed two-dimensional quantitative structure-activity relationship (2D-QSAR) and hologram QSAR (HQSAR) methods to quantitatively investigate the mechanism and active site of toxicity for Danio rerio exposed to triazole fungicides. Our results showed that 2D-QSAR models constructed using the energy of the lowest unoccupied molecular orbit, the net C atom charges, the octanol-water partition coefficient and the molecular shape factor had higher predictive abilities. HQSAR models containing the fragment distinctions atoms (As), bonds (Bs), chirality (Ch) and donors and acceptors (D&A) had higher reliability. It was found that 2D-QSAR results explaining the toxicity mechanism were consistent with HQSAR. In summary, the hydrophobicity and shape/size of the molecule were the important factors influencing the toxic effect of these chemicals against D. rerio. In addition, electron exchange may occur between these fungicides and the target. The study provided a method to evaluate the environmental risk of chemicals with a similar structure, based on the QSAR models obtained.

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Section: Introductionsupporting

confidence: 71%

“…Results from Equations (1)- (4) showed that E LUMO was an efficient descriptor to predict the acute toxicity of these compounds in zebrafish. Chan et al found that the thiol reactivity and rat or human hepatocyte toxicity induced by substituted p-benzoquinone compounds were closely related to E LUMO [26].…”

Section: Analysis Of Toxic Mechanismmentioning

confidence: 99%

Comparative quantitative structure–activity relationship (QSAR) study on acute toxicity of triazole fungicides to zebrafish

Ding

Guo

Song

et al. 2011

Chemistry and Ecology

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“…On the surface of boron-doped diamond electrodes, OH radicals are formed at a potential of 2500 mV (Kraft, 2007). These electrophilic species are known to interact with electrons of chlorinated aromatic compounds (Vrtacnik and Voda, 2003), yielding different hydroxylated and dechlorinated oxidation products (Liu et al, 2009). In vivo, dechlorination reactions have been described for several polychlorinated hydrocarbons, such as the polychlorinated biphenyls (Schnellmann et al, 1984;Ariyoshi et al, 1997;Haraguchi et al, 2005).…”

Section: Electrochemical Studies Of Tcc Show Reactive Metabolitesmentioning

confidence: 99%

Electrochemistry-Mass Spectrometry Unveils the Formation of Reactive Triclocarban Metabolites

Baumann¹,

Lohmann²,

Rose³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Triclocarban (3,4,4-trichlorocarbanilide, TCC) is a widely used antibacterial agent in personal care products and is frequently detected as an environmental pollutant in waste waters and surface waters. In this study, we report novel reactive metabolites potentially formed during biotransformation of TCC. The oxidative metabolism of TCC has been predicted using an electrochemical cell coupled online to liquid chromatography and electrospray ionization mass spectrometry. The electrochemical oxidation unveils the fact that hydroxylated metabolites of TCC may form reactive quinone imines. Moreover, a so-far unknown dechlorinated and hydroxylated TCC metabolite has been identified. The results were confirmed by in vitro studies with human and rat liver microsomes. The reactivity of the newly discovered quinone imines was demonstrated by their covalent binding to glutathione and macromolecules, using ␤-lactoglobulin A as a model protein. The results regarding the capability of the electrochemical cell to mimic the oxidative metabolism of TCC are discussed. Moreover, the occurrence of reactive metabolites is compared with findings from earlier in vivo studies and their relevance in vivo is argued.

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“…The strategy of combining 3D contour maps with the structural environment of the protein (target binding site) has proven useful to investigate important parameters such as affinity and potency, but can also be used to study other pharmacodymanic and pharmacokinetic properties, including selectivity, reactivity and metabolism [71,107,[119][120][121][122][123][124][125][126][127]. Furthermore, considering that the QSAR models may provide useful insights into structural and chemical features related to the property of interest (biological activity parameter), it is possible to envisage that the same general approach can be applied in SBVS for the identification of hits [128][129][130][131].…”

Section: Structure-based Lead Optimizationmentioning

confidence: 99%

Structure-Based Drug Design Strategies in Medicinal Chemistry

Andricopulo¹,

Salum²,

Abraham

2009

CTMC

138

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A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds.Keywords: Structure-based drug design, medicinal chemistry, virtual screening, QSAR, pharmacophores. STRUCTURE-BASED DRUG DESIGNThe performance of biochemical processes and cell mechanisms are dependent upon complex and multiple noncovalent intermolecular interactions between proteins and small-molecule modulators. The understanding of the structural and chemical binding properties of important drug targets in biologically relevant pathways allows the design of small molecules capable of regulating or modulating specific target functions in the body that are closely linked to human diseases and disorders, through multiple intermolecular interactions within a well-defined binding pocket [1][2][3][4]. In general, the identification of promising hits for further optimization is a major challenge faced by the both pharmaceutical and academic laboratories. Although the trial-anderror nature is inherent in drug research, rational concepts and modern computational methods have become widely employed for lead selection and optimization.The use of three-dimensional (3D) protein structure information in the development of new biologically active molecules, which is termed Structure-Based Drug Design (SBDD), is a well-established, successful and highly attarctive strategy used by academic and pharmaceutical research laboratories worldwide [3][4][5][6][7][8]. As a creative and knowledgedriven approach, an essential requirement for structure-based studies is a substantial understanding of the spatial and energetic aspects that affect the binding affinities of proteinligand complexes. Considering that the shape and chemical nature of the binding site of a specific target protein are known, and the possible intermolecular interactions between ligands and the protein within its active site have been identified, this qualified information can be directly employed for the identification of new ligands and the optimization of lead compounds. This opens new possibilities to boost the search for lead molecules and to limit the number of compounds that need to be evaluated experimentally.Hits can be identified through the docking of smallmolecule ligands (selected from databases of chemical structures) into protein active sites or by using receptorbased pharmacophore models. Furthermore, drug candidates can be designed de novo by improving the complementary binding properties of lead compounds and the r...

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HQSAR and CoMFA approaches in predicting reactivity of halogenated compounds with hydroxyl radicals

Cited by 11 publications

References 18 publications

Comparative quantitative structure–activity relationship (QSAR) study on acute toxicity of triazole fungicides to zebrafish

Comparative quantitative structure–activity relationship (QSAR) study on acute toxicity of triazole fungicides to zebrafish

Electrochemistry-Mass Spectrometry Unveils the Formation of Reactive Triclocarban Metabolites

Structure-Based Drug Design Strategies in Medicinal Chemistry

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