Skin Sensitization Prediction Using Quantum Chemical Calculations: A Theoretical Model for the S_NAr Domain

It is widely accepted that skin sensitization begins with the sensitizer in question forming a covalent adduct with a protein electrophile or nucleophile. We investigate the use of quantum chemical methods in an attempt to rationalize the sensitization potential of chemicals of the S_NAr reaction domain. We calculate the full reaction profile for 23 chemicals with experimental sensitization data. For all quantitative measurements, we find that there is a good correlation between the reported pEC3 and the calculated barrier to formation of the low energy product or intermediate (<i>r</i>² = 0.64, <i>N</i> = 12) and a stronger one when broken down by specific subtype (<i>r</i>² > 0.9). Using a barrier cutoff of ∼10 kcal/mol allows us to categorize 100% (<i>N</i> = 12) of the sensitizers from the nonsensitizers (<i>N</i> = 11), with just 1 nonsensitizer being mispredicted as a weak sensitizer (9%). This model has an accuracy of ∼96%, with a sensitivity of 100% and a specificity of ∼91%. We find that the kinetic and thermodynamic information provided by the complete profile can help in the rationalization process, giving additional insight into a chemical’s potential for skin sensitization

Skin Sensitization Prediction Using Quantum Chemical Calculations: A Theoretical Model for the S_NAr Domain

It is widely accepted that skin sensitization begins with the sensitizer in question forming a covalent adduct with a protein electrophile or nucleophile. We investigate the use of quantum chemical methods in an attempt to rationalize the sensitization potential of chemicals of the S_NAr reaction domain. We calculate the full reaction profile for 23 chemicals with experimental sensitization data. For all quantitative measurements, we find that there is a good correlation between the reported pEC3 and the calculated barrier to formation of the low energy product or intermediate (<i>r</i>² = 0.64, <i>N</i> = 12) and a stronger one when broken down by specific subtype (<i>r</i>² > 0.9). Using a barrier cutoff of ∼10 kcal/mol allows us to categorize 100% (<i>N</i> = 12) of the sensitizers from the nonsensitizers (<i>N</i> = 11), with just 1 nonsensitizer being mispredicted as a weak sensitizer (9%). This model has an accuracy of ∼96%, with a sensitivity of 100% and a specificity of ∼91%. We find that the kinetic and thermodynamic information provided by the complete profile can help in the rationalization process, giving additional insight into a chemical’s potential for skin sensitization

Skin Sensitization Prediction Using Quantum Chemical Calculations: A Theoretical Model for the S_NAr Domain

It is widely accepted that skin sensitization begins with the sensitizer in question forming a covalent adduct with a protein electrophile or nucleophile. We investigate the use of quantum chemical methods in an attempt to rationalize the sensitization potential of chemicals of the S_NAr reaction domain. We calculate the full reaction profile for 23 chemicals with experimental sensitization data. For all quantitative measurements, we find that there is a good correlation between the reported pEC3 and the calculated barrier to formation of the low energy product or intermediate (<i>r</i>² = 0.64, <i>N</i> = 12) and a stronger one when broken down by specific subtype (<i>r</i>² > 0.9). Using a barrier cutoff of ∼10 kcal/mol allows us to categorize 100% (<i>N</i> = 12) of the sensitizers from the nonsensitizers (<i>N</i> = 11), with just 1 nonsensitizer being mispredicted as a weak sensitizer (9%). This model has an accuracy of ∼96%, with a sensitivity of 100% and a specificity of ∼91%. We find that the kinetic and thermodynamic information provided by the complete profile can help in the rationalization process, giving additional insight into a chemical’s potential for skin sensitization

Probing the Catalytic Mechanism Involved in the Isocitrate Lyase Superfamily: Hybrid Quantum Mechanical/Molecular Mechanical Calculations on 2,3-Dimethylmalate Lyase

The isocitrate lyase (ICL) superfamily catalyzes the cleavage of the C(2)–C(3) bond of various α-hydroxy acid substrates. Members of the family are found in bacteria, fungi, and plants and include ICL itself, oxaloacetate hydrolase (OAH), 2-methylisocitrate lyase (MICL), and (2<i>R</i>,3<i>S</i>)-dimethylmalate lyase (DMML) among others. ICL and related targets have been the focus of recent studies to treat bacterial and fungal infections, including tuberculosis. The catalytic process by which this family achieves C(2)–C(3) bond breaking is still not clear. Extensive structural studies have been performed on this family, leading to a number of plausible proposals for the catalytic mechanism. In this paper, we have applied quantum mechanical/molecular mechanical (QM/MM) methods to the most recently reported family member, DMML, to assess whether any of the mechanistic proposals offers a clear energetic advantage over the others. Our results suggest that Arg161 is the general base in the reaction and Cys124 is the general acid, giving rise to a rate-determining barrier of approximately 10 kcal/mol

Synthesis of Substituted 2‑Arylindanes from <i>E</i>‑(2-Stilbenyl)methanols via Lewis Acid-Mediated Cyclization and Nucleophililc Transfer from Trialkylsilyl Reagents

A preparative method for the synthesis of functionalized 2-arylindanes has been developed via the Lewis acid-mediated ring closure of stilbenyl methanols followed by nucleophilic transfer from trialkylsilyl reagents. The reactions gave the corresponding products in moderate to high yields and diastereoselectivity. The solvent as well as the nucleophile played an important role in determining the type(s) of product arising either from nucleophilic addition (indanes) or loss of a proton β to the indanyl-type carbocations (indenes). Electron-donating groups on the fused aromatic ring (Y and Z = OMe) or the presence of electron-withdrawing groups (NO₂) on the nonfused Ar ring facilitate the cyclization. In contrast, the presence of electron-donating groups (OMe) on the nonfused Ar ring impedes the process. In the case of Cl on the nonfused Ar ring, temperature modulates the resonance versus inductive field effects on the overall reaction pathways involving cyclization to form the indanyl-type cation. Quantum chemical calculations supported the intermediacy of the carbocation species and the transfer of hydride from triethylsilane (Nu = H) to the indanyl-type cations to form the <i>trans</i>-1,2-disubstituted indane as the single diastereomer product

Synthesis of Substituted 2‑Arylindanes from <i>E</i>‑(2-Stilbenyl)methanols via Lewis Acid-Mediated Cyclization and Nucleophililc Transfer from Trialkylsilyl Reagents

A preparative method for the synthesis of functionalized 2-arylindanes has been developed via the Lewis acid-mediated ring closure of stilbenyl methanols followed by nucleophilic transfer from trialkylsilyl reagents. The reactions gave the corresponding products in moderate to high yields and diastereoselectivity. The solvent as well as the nucleophile played an important role in determining the type(s) of product arising either from nucleophilic addition (indanes) or loss of a proton β to the indanyl-type carbocations (indenes). Electron-donating groups on the fused aromatic ring (Y and Z = OMe) or the presence of electron-withdrawing groups (NO₂) on the nonfused Ar ring facilitate the cyclization. In contrast, the presence of electron-donating groups (OMe) on the nonfused Ar ring impedes the process. In the case of Cl on the nonfused Ar ring, temperature modulates the resonance versus inductive field effects on the overall reaction pathways involving cyclization to form the indanyl-type cation. Quantum chemical calculations supported the intermediacy of the carbocation species and the transfer of hydride from triethylsilane (Nu = H) to the indanyl-type cations to form the <i>trans</i>-1,2-disubstituted indane as the single diastereomer product

An influenza A virus agglutination test using antibody-like polymers

<p>Antibodies are commonly used in diagnostic routines to identify pathogens. The testing protocols are relatively simple, requiring a certain amount of a specific antibody to detect its corresponding pathogen. Antibody functionality can be mimicked by synthesizing molecularly imprinted polymers (MIPs), i.e. polymers that can selectively recognize a given template structure. Thus, MIPs are sometimes termed ‘plastic antibody (PA)’. In this study, we have synthesized new granular MIPs using influenza A virus templates by precipitation polymerization. The selective binding of influenza A to the MIP particles was assessed and subsequently contrasted with other viruses. The affinities of influenza A virus towards the MIP was estimated based on an agglutination test by measuring the amount of influenza subtypes absorbed onto the MIPs. The MIPs produced using the H1N1 template showed specific reactivity to H1N1 while those produced using H5N1 and H3N2 templates showed cross-reactivity.</p