Theoretical study of the interaction between the antibiotic linezolid and the active site of the 50S ribosomal subunit of the bacterium Haloarcula marismortui.

First antibiotic in the oxazolidinone class, linezolid fights gram-positive multiresistant bacteria by inhibiting protein synthesis through its interaction with the 50S subunit of the functional bacterial ribosome. For its antimicrobial action, it is necessary that its chiral carbon located in the oxazolidinone ring is in the S-conformation. Computational calculation at time-dependent density functional theory methodology, ultraviolet-visible (UV-Vis), and electronic circular dichroism spectra was obtained for noncomplexed and complexed forms of linezolid to verify the possible chirality of nitrogen atom in the acetamide group of the molecule. The molecular system has two chiral centers. So, there are now four possible configurations: RR, RS, SR, and SS. For a better understanding of the system, the electronic spectra at the PBE0/6-311++G(3df,2p) level of theory were obtained. The complexed form was obtained from the crystallographic data of the ribosome, containing the S-linezolid molecular system. The computational results obtained for the electronic properties are in good agreement with the experimental crystallographic data and available theoretical results.

Designing boron and metal complexes for fluoride recognition: a computational perspective.

Fluoride anions (F-) may have beneficial or harmful effects on the environment depending on their concentration. Here, we shed light on F- recognition by compounds containing boron, tellurium and antimony, which were experimentally demonstrated to be capable of interacting with the F- ion in a partially aqueous medium. Boron and metal complexes recognize F- anions primarily using electrostatic energy along with important contributions from orbital interaction energy. The natural orbitals for chemical valence (NOCV) methodology indicates that the main orbital interactions behind fluoride recognition are σ bonds between the receptors and the F- anions. The charged receptors, which provide (i) two B atoms, (ii) one B atom and one Sb atom, or (iii) one B atom and one Te atom to directly interact with the F- ions, appear to be some of the best structures for the recognition of F- anions. This is supported by the combination of favorable electrostatic and σ bond interactions. Overall, the presence of electron donor groups, such as -CH3 and -OH, in the receptor structure destabilizes the fluoride recognition because it decreases the attractive electrostatic energy and increases the Pauli repulsion energy in the receptor⋯F- bonds. Notably, electron acceptor groups, for example, -CN and -NO2, in the receptor structure favor the interaction with the F- ions, due to the improvement of the electrostatic and σ bond interactions. This study opens the way to find the main features of a receptor for F- recognition.

Methyl divanillate: redox properties and binding affinity with albumin of an antioxidant and potential NADPH oxidase inhibitor.

Vanillic acid is a widely used food additive (flavouring agent, JECFA number: 959) with many reported beneficial biological effects. The same is true for its ester derivative (methyl vanillate, JECFA number: 159). Based on the increasing evidence that diapocynin, the dimer of apocynin (NADPH oxidase inhibitor), has some improved pharmacological properties compared to its monomer, here the dimer of methyl vanillate (MV), i.e., methyl divanillate (dimer of methyl vanillate, DMV) was synthesized and studied in the context of its redox properties and binding affinity with human serum albumin (HSA). We found that the antioxidant potency of DMV was significantly increased compared to MV. In this regard, the reduction of 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical by DMV was 30-fold more effective compared to MV. Ferric ion reduction was 4-fold higher and peroxyl radical reduction was 2.7-fold higher. The interaction with HSA was significantly improved (Stern-Vomer constants, 3.8 × 105 mol-1 L and 2.3 × 104 mol-1 L, for DMV and MV, respectively). The complexation between DMV and HSA was also evidenced by induced circular dichroism (ICD) signal generation in the former due to its fixation in the asymmetric protein pocket. Density-functional calculations (TD-DFT) showed that the ICD spectrum was related to a DMV conformation bearing a dihedral angle of approximately -60°. Similar dihedral angles were obtained in the lowest and most populated DMV cluster poses obtained by molecular docking simulations. The computational studies and experimental displacement studies revealed that DMV binds preferentially at site I. In conclusion, besides being a powerful antioxidant, DMV is also a strong ligand of HSA. This is the first study on the chemical and biophysical properties of DMV, a compound with potential beneficial biological effects.

Solvent-dependent inversion of circular dichroism signal in naproxen: An unusual effect!

The electronic circular dichroism (ECD) spectra of naproxen enantiomers were studied as a function of solvents using experimental (circular dichroism) and theoretical (time-dependent density functional theory) approaches. The (R)- and (S)-naproxen enantiomers presented an unusual inversion in their ECD signals in the presence of ethanol and water when compared with polar aprotic solvents such as acetonitrile. From a practical point of view, these findings deserve great attention because these solvents are widely used for high-performance liquid chromatography analysis in quality control of chiral pharmaceutical drugs. This is particularly relevant to naproxen because the (S)-naproxen has anti-inflammatory properties, whereas (R)-naproxen is hepatotoxic. A time-dependent density functional theory computer simulation was conducted to investigate the signal inversion using the solvation model based on density, a reparameterization of polarized continuum model. Electronic circular dichroism signals of conformers were calculated by computer simulation and their contribution to the combined spectra obtained according to Boltzmann weighting. It was found that the experimentally observed ECD signal inversion can be associated with the minor or major contribution of different conformers of naproxen.

Induction of axial chirality in divanillin by interaction with bovine serum albumin.

Vanillin is a plant secondary metabolite and has numerous beneficial health applications. Divanillin is the homodimer of vanillin and used as a taste enhancer compound and also a promissory anticancer drug. Here, divanillin was synthesized and studied in the context of its interaction with bovine serum albumin (BSA). We found that divanillin acquires axial chirality when complexed with BSA. This chiroptical property was demonstrated by a strong induced circular dichroism (ICD) signal. In agreement with this finding, the association constant between BSA and divanillin (3.3 x 105 mol-1L) was higher compared to its precursor vanillin (7.3 x 104 mol-1L). The ICD signal was used for evaluation of the association constant, demonstration of the reversibility of the interaction and determination of the binding site, revealing that divanillin has preference for Sudlow's site I in BSA. This property was confirmed by displacement of the fluorescent markers warfarin (site I) and dansyl-L-proline (site II). Molecular docking simulation confirmed the higher affinity of divanillin to site I. The highest scored conformation obtained by docking (dihedral angle 242°) was used for calculation of the circular dichroism spectrum of divanillin using Time-Dependent Density Functional Theory (TDDFT). The theoretical spectrum showed good similarity with the experimental ICD. In summary, we have demonstrated that by interacting with the chiral cavities in BSA, divanillin became a atropos biphenyl, i.e., the free rotation around the single bound that links the aromatic rings was impeded. This phenomenon can be explained considering the interactions of divanillin with amino acid residues in the binding site of the protein. This chiroptical property can be very useful for studying the effects of divanillin in biological systems. Considering the potential pharmacological application of divanillin, these findings will be helpful for researchers interested in the pharmacological properties of this compound.

Taurine Bromamine: Reactivity of an Endogenous and Exogenous Anti-Inflammatory and Antimicrobial Amino Acid Derivative.

Taurine bromamine (Tau-NHBr) is produced by the reaction between hypobromous acid (HOBr) and the amino acid taurine. There are increasing number of applications of Tau-NHBr as an anti-inflammatory and microbicidal drug for topical usage. Here, we performed a comprehensive study of the chemical reactivity of Tau-NHBr with endogenous and non-endogenous compounds. Tau-NHBr reactivity was compared with HOBr, hypochlorous acid (HOCl) and taurine chloramine (Tau-NHCl). The second-order rate constants (k2) for the reactions between Tau-NHBr and tryptophan (7.7 × 10² M(-1)s(-1)), melatonin (7.3 × 10³ M(-1)s(-1)), serotonin (2.9 × 10³ M(-1)s(-1)), dansylglycine (9.5 × 10¹ M(-1)s(-1)), tetramethylbenzidine (6.4 × 10² M(-1)s(-1)) and H2O2 (3.9 × M(-1)s(-1)) were obtained. Tau-NHBr demonstrated the following selectivity regarding its reactivity with free amino acids: tryptophan > cysteine ~ methionine > tyrosine. The reactivity of Tau-NHBr was strongly affected by the pH of the medium (for instance with dansylglycine: pH 5.0, 1.1 × 104 M(-1)s(-1), pH 7.0, 9.5 × 10 M(-1)s(-1) and pH 9.0, 1.7 × 10 M(-1)s(-1)), a property that is related to the formation of the dibromamine form at acidic pH (Tau-NBr2). The formation of singlet oxygen was observed in the reaction between Tau-NHBr and H2O2. Tau-NHBr was also able to react with linoleic acid, but with low efficiency compared with HOBr and HOCl. Compared with HOBr, Tau-NHBr was not able to react with nucleosides. In conclusion, the following reactivity sequence was established: HOBr > HOCl > Tau-NHBr > Tau-NHCl. These findings can be very helpful for researchers interested in biological applications of taurine haloamines.

G3(MP2)-CEP theory and applications for compounds containing atoms from representative first, second and third row elements of the periodic table.

The compact effective potential (CEP) pseudopotential was adapted to the G3(MP2) theory, herein referred to as G3(MP2)-CEP, and applied to the calculation of enthalpies of formation, ionization energies, atomization energies, and electron and proton affinities for 446 species containing elements of the 1st, 2nd, and 3rd rows of the periodic table. A total mean absolute deviation of 1.67 kcal mol(-1) was achieved with G3(MP2)-CEP, compared with 1.47 kcal mol(-1) for G3(MP2). Electron affinities and enthalpies of formation are the properties exhibiting the lowest deviations with respect to the original G3(MP2) theory. The use of pseudopotentials and composite theories in the framework of the G3 theory is feasible and compatible with the all electron approach. Graphical Abstract Application of composite methods in high-level ab initio calculations.

Hypobromous acid, a powerful endogenous electrophile: Experimental and theoretical studies.

Hypobromous acid (HOBr) is an inorganic acid produced by the oxidation of the bromide anion (Br(-)). The blood plasma level of Br(-) is more than 1,000-fold lower than that of chloride anion (Cl(-)). Consequently, the endogenous production of HOBr is also lower compared to hypochlorous acid (HOCl). Nevertheless, there is much evidence of the deleterious effects of HOBr. From these data, we hypothesized that the reactivity of HOBr could be better associated with its electrophilic strength. Our hypothesis was confirmed, since HOBr was significantly more reactive than HOCl when the oxidability of the studied compounds was not relevant. For instance: anisole (HOBr, k2=2.3×10(2)M(-1)s(-1), HOCl non-reactive); dansylglycine (HOBr, k2=7.3×10(6)M(-1)s(-1), HOCl, 5.2×10(2)M(-1)s(-1)); salicylic acid (HOBr, k2=4.0×10(4)M(-1)s(-1), non-reactive); 3-hydroxybenzoic acid (HOBr, k2=5.9×10(4)M(-1)s(-1), HOCl, k2=1.1×10(1)M(-1)s(-1)); uridine (HOBr, k2=1.3×10(3)M(-1)s(-1), HOCl non-reactive). The compounds 4-bromoanisole and 5-bromouridine were identified as the products of the reactions between HOBr and anisole or uridine, respectively, i.e. typical products of electrophilic substitutions. Together, these results show that, rather than an oxidant, HOBr is a powerful electrophilic reactant. This chemical property was theoretically confirmed by measuring the positive Mulliken and ChelpG charges upon bromine and chlorine. In conclusion, the high electrophilicity of HOBr could be behind its well-established deleterious effects. We propose that HOBr is the most powerful endogenous electrophile.

Assessment of G3(MP2)∕∕B3 theory including a pseudopotential for molecules containing first-, second-, and third-row representative elements.

G3(MP2)∕∕B3 theory was modified to incorporate compact effective potential (CEP) pseudopotentials, providing a theoretical alternative referred to as G3(MP2)∕∕B3-CEP for calculations involving first-, second-, and third-row representative elements. The G3∕05 test set was used as a standard to evaluate the accuracy of the calculated properties. G3(MP2)∕∕B3-CEP theory was applied to the study of 247 standard enthalpies of formation, 104 ionization energies, 63 electron affinities, 10 proton affinities, and 22 atomization energies, comprising 446 experimental energies. The mean absolute deviations compared with the experimental data for all thermochemical results presented an accuracy of 1.4 kcal mol(-1) for G3(MP2)∕∕B3 and 1.6 kcal mol(-1) for G3(MP2)∕∕B3-CEP. Approximately 75% and 70% of the calculated properties are found with accuracy between ±2 kcal mol(-1) for G3(MP2)∕∕B3 and G3(MP2)∕∕B3-CEP, respectively. Considering a confidence interval of 95%, the results may oscillate between ±4.2 kcal mol(-1) and ±4.6 kcal mol(-1), respectively. The overall statistical behavior indicates that the calculations using pseudopotential present similar behavior with the all-electron theory. Of equal importance to the accuracy is the CPU time, which was reduced by between 10% and 40%.

Implementation of pseudopotential in the G3 theory for molecules containing first-, second-, and non-transition third-row atoms.

Compact effective pseudopotential (CEP) is adapted in the G3 theory providing a theoretical alternative referred to as G3CEP for calculations involving the first-, second-, and non-transition third-row elements. These modifications tried to preserve as much as possible the original characteristics of G3. G3CEP was used in the study of 247 enthalpies of formation, 22 atomization energies, 104 ionization potentials, 63 electron affinities, and 10 proton affinities, resulting in the calculation of 446 species for the first-, second-, and third-row atoms. The final average total absolute deviation was of 1.29 kcal mol(-1) against 1.16 kcal mol(-1) from all-electron G3 for the same calculations. The CPU time has been reduced by 7% to 56%, depending on the size of the molecules and the type of atoms considered.