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(A) This figure illustrates the conjugated a,b-unsaturated carbonyl structure of chemicals in the Type-2 alkene class. (B) This figure presents the corresponding line structures for ACR and the structurally related Type-2 alkenes used in the present study (left column). Also shown are the nonconjugated structural analogs used (right column).
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Conjugated Type-2 alkenes, such as acrylamide (ACR), are soft electrophiles that produce neurotoxicity by forming adducts with soft nucleophilic sulfhydryl groups on proteins. Soft-soft interactions are governed by frontier molecular orbital characteristics and can be defined by quantum mechanical parameters such as softness (sigma) and chemical po...
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... determine how electrophilic softness was related to sulfhydryl reactivity, we compared selected quantum mechan- ical parameters to kinetic data. The LUMO energies (E LUMO ) and the HOMO energies (E HOMO ) for the Type-2 alkenes and their nonconjugated analogs (Fig. 1B) were calculated using commercially available software (Spartan04; Wavefunction, Inc.). The calculated energy values were then used to compute the softness (r) of each electrophile (Table 1). Softness is considered the ease with which electron redistribution takes place during covalent bonding and thus, the softer the electrophile, the ...
Citations
... Olefins 1, 2, 3, 5−12, and 14 have been previously calculated by others. 6,27,31,35,42 The acrylamides 15 and 16H are the truncated forms of afatinib, while 17 and 18H are their respective isomers; 29 is a deactivated form with a α-methyl substitution inspired by the work of Tsou et al. 38 Starting from these olefins, additional ones taken from other literature (e.g., ref 22) were added to fill in the gaps in the ΔG ‡ data range. Together, the ΔG ‡ values range from about 7 to 23 kcal/mol ( Figure S1), corresponding to a rate constant range of 7.3 × 10 −5 s −1 to 4.5 × 10 7 s −1 . ...
... The two-dimensional structures of 33 singly-and doublyactivated olefins are given in Table 1. Some of these compounds were taken from the literature, 6,27,31,35,42 and some of them are related to the FDA-approved drug afatinib or the covalent warheads for EGFR. 38 To avoid bias in the correlation study, additional model compounds were added such that the reaction barriers were evenly distributed between approximately 7 and 23 kcal/mol. ...
Predictive modeling and understanding of chemical warhead reactivities have the potential to accelerate targeted covalent drug discovery. Recently, the carbanion formation free energies as well as other ground-state electronic properties from density functional theory (DFT) calculations have been proposed as predictors of glutathione reactivities of Michael acceptors; however, no clear consensus exists. By profiling the thiol-Michael reactions of a diverse set of singly- and doubly-activated olefins, including several model warheads related to afatinib, here we reexamined the question of whether low-cost electronic properties can be used as predictors of reaction barriers. The electronic properties related to the carbanion intermediate were found to be strong predictors, e.g., the change in the Cβ charge accompanying carbanion formation. The least expensive reactant-only properties, the electrophilicity index, and the Cβ charge also show strong rank correlations, suggesting their utility as quantum descriptors. A second objective of the work is to clarify the effect of the β-dimethylaminomethyl (DMAM) substitution, which is incorporated in the warheads of several FDA-approved covalent drugs. Our data suggest that the β-DMAM substitution is cationic at neutral pH in solution and promotes acrylamide's intrinsic reactivity by enhancing the charge accumulation at Cα upon carbanion formation. In contrast, the inductive effect of the β-trimethylaminomethyl substitution is diminished due to steric hindrance. Together, these results reconcile the current views of the intrinsic reactivities of acrylamides and contribute to large-scale predictive modeling and an understanding of the structure-activity relationships of Michael acceptors for rational TCI design.
... Olefins 1, 2, 3, 5-12, and 14 have been previously calculated by others. 6,27,31,35,42 The acrylamides 15 and 16H are the truncated forms of afatinib, while 17 and 18H are their respective isomers and 29 is a deactivated form with a α-methyl substitution inspired by the work of Tsou et al. 38 Starting from these olefins, additional ones taken from other literature (e.g., Ref. 22 ) were added to fill in the gaps in the ∆G ‡ data range. Together, the ∆G ‡ values range from about 7 to 23 kcal/mol (Fig. S1), corresponding to a rate constant range of 7.3 × 10 −5 s −1 to 4.5 × 10 7 s −1 . ...
... The two-dimensional structures of 30 singly-and doubly-activated olefins are given in Table 1. Some of these compounds were taken from literature, 6,27,31,35,42 and some of them are related to the FDA-approved drug afatinib or the covalent warheads for EGFR. 38 To avoid bias in the correlation study, additional model compounds were added such that the reaction barriers evenly distribute between approximately 7 and 23 kcal/mol. ...
Predictive modeling and understanding chemical warhead reactivities have the potential to accelerate targeted covalent drug discovery. Recently, the carbanion formation free energies as well as other ground-state electronic properties from the den- sity functional theory (DFT) calculations have been proposed as predictors of glutathione reactivities of Michael acceptors; however, no clear consensus exists. By profiling the thiol-Michael reactions of a diverse set of singly- and doubly-activated olefins including several model warheads related to afatinib, here we reexamined the question of whether low-cost electronic properties can be used as predictors of reaction barriers. The electronic properties related to the carbanion intermediate were found to be strong predictors, e.g., the change in the Cβ charge accompanying carbanion formation. The least expensive reactant-only properties, the electrophilicity index and the Cβ charge also show strong rank correlations, suggesting their utility as quantum descriptors. A second objective of the work is to clarify the effect of the β-dimethylaminomethyl (DMAM) substitution which is incorporated in the warheads of several FDA-approved covalent drugs. Our data suggests that the beta-DMAM substitution is cationic at neutral pH in solution and it promotes acrylamide’s intrinsic reactivity by enhancing the charge accumulation at Calpha upon carbanion formation. In contrast, the inductive effect of the beta-trimethylaminomethyl substitution is diminished due to steric hindrance. Together, these results reconcile the current views of the intrinsic reactivities of acrylamides and contribute to large-scale predictive modeling and understanding of the structure-activity relationships of Michael acceptors for rational TCI design.
... It can deacetylate to form L-cysteine, the essential amino acid for synthesizing GSH. As a strong nucleophile, it can react with electrophilic groups directly through free sulfhydryl groups (LoPachin et al., 2007). As illustrated above, GSH can modify and transform toxicants. ...
Microalgae have been recognized as emerging cell factories due to the high value-added bio-products. However, the balance between algal growth and the accumulation of metabolites is always the main contradiction in algal biomass production. Hence, the security and effectiveness of regulating microalgal growth and metabolism simultaneously have drawn substantial attention. Since the correspondence between microalgal growth and reactive oxygen species (ROS) level has been confirmed, improving its growth under oxidative stress and promoting biomass accumulation under non-oxidative stress by exogenous mitigators is feasible. This paper first introduced ROS generation in microalgae and described the effects of different abiotic stresses on the physiological and biochemical status of microalgae from these aspects associated with growth, cell morphology and structure, and antioxidant system. Secondly, the role of exogenous mitigators with different mechanisms in alleviating abiotic stress was concluded. Finally, the possibility of exogenous antioxidants regulating microalgal growth and improving the accumulation of specific products under non-stress conditions was discussed.
... Some of these olefins, 1, 2, 3, 5-12, and 14, have been previously studied by others. 6,25,29,33,40 The acrylamides 15 and 16H are the truncated forms of afatinib, while 17 and 18H are their respective isomers and 29 is a deactivated form with a α-methyl substitution inspired by the work of Tsou et al. 36 Following the work of others, 21,23,25,28,29,35 7 methanethiolate was used as the model reactive thiolate. Note, glutathione (GSH) is commonly used in the experimental studies of the intrinsic reactivities of warheads. ...
... The two-dimensional structures of 30 singly-and doubly-activated olefins are given in Table 1. Some of these compounds were taken from literature, 6,25,29,33,40 and some of them are related to the FDA-approved drug afatinib or the covalent warheads for EGFR. 36 To avoid bias in the correlation study, additional model compounds were added such that the reaction barriers evenly distribute between approximately 7 and 23 kcal/mol. ...
Predictive modeling and understanding chemical warhead reactivities have the potential to accelerate targeted covalent drug discovery. Here we used density functional theory calculations to reexamine the ground-state quantum descriptors and important structure-activity (SAR) relationships of thiol-Michael additions. The calculated reaction profiles of the singly- and doubly-activated olefins including several model warheads related to afatinib revealed strong correlations between the reaction barriers and electronic properties related to the carbanion intermediate. Among them the change in the Cb charge upon carbanion formation is the strongest reactivity predictor, while the least expensive reactant-only properties, the electrophilicity index and the carbon charge also show strong rank correlations, suggesting their utility as quantum descriptors for building machine learning models. We also investigated the reactivity enhancement effect of the beta-dimethylaminomethyl (DMAM) substitution which led to several FDA-approved covalent drugs. Our data revealed that the -DMAM substitution is protonated at neutral pH and it lowers the reaction barrier through inducing the charge accumulation at the C upon carbanion formation; by contrast, the inductive effect of the beta-trimethylaminomethyl substitution is diminished due to steric hindrance. The data also suggested that the beta-DMAM substitution downshifts the thiol pKa and thereby activates EGFR’s front pocket cysteine C797 for nucleophilic attack. Taken together, our study contributes novel insights for large-scale modeling and understanding the SARs of covalent warheads.
... 4-HNE can adduct to the cysteine residue of the "flippase" enzyme (amino phospholipidtranslocase), an enzyme that maintains lipid bilayer asymmetry by an ATPdependent process [145]. Forming Michael adducts with nucleophilic sites, 4-HNE can interact with cellular DNA, lipids, and proteins [146]. The destiny of 4-HNE protein adducts is either proteolysis or covalent cross-linking. ...
The better prognosis of COVID-19 in children conferred a higher survival rate, but a higher prevalence of post-COVID sequalae, including insomnia and defective cognition. COVID-19 triggered oxidative stress, with hyperlipidemia correlated with susceptibility to severe COVID-19. Consequently, lipids peroxidation could be a likely candidate for disease progression and sequalae. Hence, this overview explored one of the commonly studied lipid peroxides, 4-hydroxynonenal (4-HNE), in terms of gamma-amino butyric acid (GABA) and glutamate. Higher glutamate and lower glutamine, a GABA substrate, triggered severe COVID-19. Increased glutamate and inflammatory cytokines induced GABA endocytosis, reducing the anti-inflammatory and antioxidant effects of GABA. Defective glutathione antioxidant was detected in Down syndrome, the latter was associated with severe COVID-19. Increased 4-HNE, due to consumption of electronic devices and flavors containing 1-bromopropane, was increased in inflammatory neurologic disorders. A higher hippocampal 4-HNE triggered excitotoxicity and cognitive deficits. Hippocampal inflammation and loss were also evident in COVID-19. 4-HNE might play role in disturbing sleep and cognition in children during COVID-19, a hypothesis that could be verified in future research by redeeming 4-HNE in the sputum and urine of children. Currently, supplying children with optimum dietary antioxidants, while rationalizing the use of flavors is to be encouraged.
... Both anilines and phenols are reactive nucleophiles (a trait that makes them photodegradable); however, as nitrogen is more likely to give up electrons than oxygen, anilines edge phenols in reactivity, which, in turn, makes them least likely to meet the E cutoff. Since most toxicants are electrophiles (28)(29)(30), we also compared the lowest unoccupied molecular orbital (LUMO) energies across the dataset and found that anilines had the lowest average (−1.92 eV) as compared to phenols (−1.89 eV), aryl ethers (−1.44 eV), and sulfides (−1.21 eV). ...
... fig. S4) (28)(29)(30). Substituting E LUMO for E in Fig. 4B (26) does just that, creating a design space for pesticides that perform well across both categories of degradation and ecotoxicity. This analysis was replicated for individual pesticide classes (phenols and anilines in fig. ...
Rational design of pesticides with tunable degradation properties and minimal ecotoxicity is among the grand challenges of green chemistry. While computational approaches have gained traction in predictive toxicology, current methods lack the necessary multifaceted approach and design-vectoring tools needed for system-based chemical development. Here, we report a tiered computational framework, which integrates kinetics and thermodynamics of indirect photodegradation with predictions of ecotoxicity and performance, based on cutoff values in mechanistically derived physicochemical properties and electronic parameters. Extensively validated against experimental data and applied to 700 pesticides on the U.S. Environmental Protection Agency's registry, our simple yet powerful approach can be used to screen existing molecules to identify application-ready candidates with desirable characteristics. By linking structural attributes to process-based outcomes and by quantifying trade-offs in safety, depletion, and performance, our method offers a user-friendly roadmap to rational design of novel pesticides.
... This peak almost disappeared in the 1 H NMR spectrum of Se-starch80, suggesting the −HC=CH− participated in the reaction. In this reaction system, NaSeH is a strong nucleophile that can undergo a reaction similar to the −SH and −HC=CH− groups [34]. While the −HC=CH− is the group with the maximum reactivity in the OSA starch toward NaSeH. ...
Selenium-functionalized starch (Se-starch80) is one of the main functional foods used for selenium supplementation. In traditional agriculture, Se-starch has some deficiencies such as long growth cycle and unstable selenium content that prevent its antioxidant performance. In this study, Se-starch was prepared by the nucleophilic addition between NaSeH and carbon-carbon double bond of octenyl succinic anhydride waxy corn starch ester (OSA starch). Some techniques such as 1HNMR, XPS, SEM-EDS, XRD and FT-IR were used to characterize the relevant samples and the results showed that the modification did not destroy the starch framework significantly and the catalytic center (negative divalent selenium) was anchored on the starch framework. The intensive distribution of catalytic center on the starch surface and the hydrophobic microenvironments derived from the OSA chains furnished the Se-starch80 with a high GPx-like catalytic activity (initial reaction rate = 3.64 μM/min). This value was about 1.5 × 105 times higher than that of a typical small-molecule GPx mimic (PhSeSePh). In addition, the Se-starch80, without any cytotoxicity, showed a saturated kinetic catalytic behavior that is similar to a typical enzyme. This work exemplifies a biodegradable selenium-functionalized polymer platform for the high-performing GPx mimic.
... The solvent parameter was set to water (pH = 7). Energy levels of the lowest unoccupied molecular orbital (ELUMO), highest occupied molecular orbital (EHOMO), and the electron density were used to measure reactive potential for the example substructure aniline and the related reactive metabolites in our analysis [32]. The ELUMO and EHOMO obtained from quantum chemistry analysis were used to calculate the global hardness η = (ELUMO − EHOMO)/2, chemical potential μ = (ELUMO + EHOMO)/2, and electrophilicity index ω = μ 2 /2η. ...
... The solvent parameter was set to water (pH = 7). Energy levels of the lowest unoccupied molecular orbital (E LUMO ), highest occupied molecular orbital (E HOMO ), and the electron density were used to measure reactive potential for the example substructure aniline and the related reactive metabolites in our analysis [32]. The E LUMO and E HOMO obtained from quantum chemistry analysis were used to calculate the global hardness η = (E LUMO − E HOMO )/2, chemical potential µ = (E LUMO + E HOMO )/2, and electrophilicity index ω = µ 2 /2η. ...
... Quantum chemistry properties have been useful in assessing reactive potential for structural alerts or chemical entities [32,50]. The culprit reactive metabolites, nitrobenzene and quinone imine, are highly reactive, as indicated by the quantum chemistry properties. ...
An effective approach for assessing a drug’s potential to induce autoimmune diseases (ADs) is needed in drug development. Here, we aim to develop a workflow to examine the association between structural alerts and drugs-induced ADs to improve toxicological prescreening tools. Considering reactive metabolite (RM) formation as a well-documented mechanism for drug-induced ADs, we investigated whether the presence of certain RM-related structural alerts was predictive for the risk of drug-induced AD. We constructed a database containing 171 RM-related structural alerts, generated a dataset of 407 AD- and non-AD-associated drugs, and performed statistical analysis. The nitrogen-containing benzene substituent alerts were found to be significantly associated with the risk of drug-induced ADs (odds ratio = 2.95, p = 0.0036). Furthermore, we developed a machine-learning-based predictive model by using daily dose and nitrogen-containing benzene substituent alerts as the top inputs and achieved the predictive performance of area under curve (AUC) of 70%. Additionally, we confirmed the reactivity of the nitrogen-containing benzene substituent aniline and related metabolites using quantum chemistry analysis and explored the underlying mechanisms. These identified structural alerts could be helpful in identifying drug candidates that carry a potential risk of drug-induced ADs to improve their safety profiles.
... nucleophiles, such as amino groups. In contrast, soft electrophiles prefer to react with soft nucleophiles, such as thiols (LoPachin et al., 2007(LoPachin et al., , 2012. In our study, metals such as MeHg and Cd were used as soft electrophiles, Cu (II), Zn, Ni, and Fe as borderline electrophiles, and Sn, Li, Sr, and Al as hard electrophiles. ...
... While molecules such as GalNAc lack features expected in a Se-binding partner, urinary Se is excreted as the selenosugar, 1β-methylseleno-N-acetyl-D-galactosamine which forms through an incompletely described reaction pathway Fig. 4 The xenobiotic E* in the environment are increasing in the number of forms and concentrations in potential exposure sources. Certain E* are common products formed during cooking of foods, others are synthetic products, contaminants, and/or metabolites of pharmaceutical agents or other E* precursors common components present in cooked foods (e.g., acrylamide) that can induce cell damage (LoPachin et al., 2007;. The unsaturated carbonyls of organic E* are known to form covalent bonds with nucleophilic Cys thiols but will have far higher affinities for Sec. ...
Electrophiles are abundant in diets and environmental exposures, but their effects on selenium (Se) metabolism have only begun to be studied. Selenium-dependent enzymes depend on the functions of selenocysteine (Sec) to perform their biochemical roles. As the most potent intracellular nucleophile, Sec is subject to binding by mercury and other electron-poor soft neurotoxic electrophiles. Humans possess 25 selenoprotein genes, approximately half of which are engaged in preventing, controlling, or reversing oxidative damage. While selenoproteins are expressed in tissue-dependent distributions and levels in all cells of all vertebrates, they are particularly important in brain development, health, and functions. Additional study is required to examine possibilities of inherited, acquired, or degenerative disorders of Se homeostasis that may influence neurological and cardiovascular vulnerability to soft electrophile exposures. Since selenoenzymes are molecular “targets” of soft electrophiles, concomitant evaluation of aggregate exposures to these toxicants must be assessed in relation to dietary Se intakes.
