In Vivo Genotoxicity and Cytotoxicity Kinetics of Trimethoprim Sulfamethoxazole in Well-nourished and Undernourished Young Rats.

BACKGROUND/AIM: Undernutrition is a serious health problem prevalent in poor countries, affecting millions of people worldwide, especially young children, pregnant women, and sick elderly individuals. This condition increases vulnerability to infections, leading to widespread use of antibiotic treatments in undernourished populations. The objective of the present study was to determine the in vivo genotoxic and cytotoxic effects of trimethoprim-sulfamethoxazole (TMP-SMX) treatment according to nutritional conditions. MATERIALS AND METHODS: The effects of TMP-SMX treatment were measured by analyzing the kinetics of micronucleated reticulocytes (MN-RET) induced in the peripheral blood of young, well-nourished (WN) and undernourished (UN) rats. RESULTS: In the WN group, two distinct peaks of MN-RET were observed, while the UN group had a significantly higher basal frequency of MN-RET compared to the WN group and only a later peak. Reticulocyte (RET) frequency slightly decreased in WN, indicating a poor cytotoxic effect. In contrast, in the UN, the treatment caused a significant increase in RET frequency. The results indicate that SMX's aromaticity index decreases when formed with TMP, suggesting potentially fewer toxic effects. CONCLUSION: In vivo TMP-SMX produces two MN-RET induction peaks in WN animals, indicating two DNA damage induction mechanisms and consequent micronucleus production. The UN rats did not display the two peaks, indicating that the first MN induction mechanism did not occur in UN, possibly due to pharmacokinetic effects, decreased metabolism or effects on cell proliferation. TMP-SMX has a slight cytotoxic effect on WN. In contrast, in the UN, the antibiotic treatment seems to favor early erythropoiesis.

The role of ETFS amino acids on the stability and inhibition of p53-MDM2 complex of anticancer p53-derivatives peptides: Density functional theory and molecular docking studies.

Cancer is one of the leading causes of mortality in the world. Despite the existence of diverse antineoplastic treatments, these do not possess the expected efficacy in many cases. Knowledge of the molecular mechanisms involved in tumor processes allows the identification of a greater number of therapeutic targets employed in the study of new anticancer drugs. In the last decades, peptide-based therapy design using computational chemistry has gained importance in the field of oncology therapeutics. This work aims to evaluate the electronic structure, physicochemical properties, stability, and inhibition of ETFS amino acids and peptides derived from the p53-MDM2 binding domain with action in cancer cells; by means of chemical descriptors at the DFT-BHandHLYP level in an aqueous solution, and its intermolecular interactions through molecular docking studies. The results show that The ETFS fragment plays a critical role in the intermolecular interactions. Thus, the amino acids E17, T18 and S20 increase intermolecular interactions through hydrogen bonds and enhance structural stability. F19, W23 and V25 enhance the formation of the alpha-helix. The hydrogen bonds formed by the backbone atoms for PNC-27, PNC-27-B and PNC-28 stabilize the α-helices more than hydrogen bonds formed by the side chains atoms. Also, molecular docking indicated that the PNC27B-MDM2, PNC28B-MDM2, PNC27-MDM2 and PNC28A-MDM2 complexes show the best binding energy. Therefore, DFT and molecular docking studies showed that the proposed peptides: PNC-28B, PNC-27B and PNC-28A could inhibit the binding of MDM2 to the p53 protein, decreasing the translocation and degradation of p53 native protein.

Adsorption of Capsaicin into the Nanoconfined Interlayer Space of Montmorillonite by DFT Calculations.

Capsaicin is the main compound responsible of the hot sense of the chili fruits. This compound has interesting therapeutic properties including anticancer, anti-inflammatory effects, and analgesic. However, its use has several secondary effects, such as skin irritation and allergies. Then, new therapeutic strategies are searched in order to overcome these problems. Montmorillonite has proved to be an excellent excipient for the release of pharmaceutical drugs. In this work, the molecular structure and crystal structure of capsaicin, and the adsorption of this molecule into the interlayer space of montmorillonite have been studied using quantum mechanical calculations based on Density Functional Theory (DFT) level of theory and molecular dynamics simulations. The crystal structure has been predicted with these calculations and the intermolecular interactions have been determined with a higher resolution than the previous experimental data. The adsorption of capsaicin into the confined interlayer space of montmorillonite is energetically favourable with low and high octahedral charge. This adsorption can be monitored by IR spectroscopy observing frequency shifts in some bands during the adsorption. This enhances the use of these clay minerals for capsaicin therapeutic formulations.

Crystal polymorphism and spectroscopical properties of sulfonamides in solid state by means of First Principles calculations.

Sulfonamides are an important class of therapeutic agents. The increase in the number of new sulfonamide derivatives makes it necessary to study more rationally the chemical structure, because the solid forms often display different mechanical, thermal and physicochemical properties that can influence the bioavailability and stability of the drugs; consequently, the polymorphic structures are of great interest to the pharmaceutical industry because of their ability to modify the physical properties of the active pharmaceutical ingredient. The molecular interactions of these drugs in their crystal lattice are important for the stability of the crystals and polymorphism and for preparing composite complexes for optimizing the use of these drugs. In this work, the crystal structure of these drugs and crystal polymorphism is investigated. So, the crystal forms of antibiotics derivatives of the sulfonamides, sulfamethoxazole, sulfamethazine, sulfachloropyridazine, and sulfacetamide are studied at the molecular and supramolecular level by using computational modeling approach at quantum mechanical level. The spectroscopic properties of these systems are also studied explaining assignments of previous experimental data. The results of DFT calculations reproduce the crystal structures of sulfonamides determined experimentally and the polymorphism in these molecules have been clarified. Likewise, the main intermolecular interactions in all crystal forms of these sulfonamides are H-bonds among the sulfonic and amino groups and SNH groups, and also some π-π interactions. Also, these 3-D periodical models allow the exploration of the intermolecular interactions included in the crystal structures and some of these interactions can alter the vibration modes of the molecules. Therefore, the use of these models can be useful for experimental spectroscopy studies where use actual crystal solids.

Imidazole and nitroimidazole derivatives as NADH-fumarate reductase inhibitors: Density functional theory studies, homology modeling, and molecular docking.

Chagas disease is caused by Trypanosoma cruzi. Benznidazole and nifurtimox are drugs used for its therapy; nevertheless, they have collateral effects. NADH-fumarate (FUM) reductase is a potential pharmacological target since it is essential for survival of parasite and is not found in humans. The objectives are to design and characterize the electronic structure of imidazole and nitroimidazole derivatives at DFT-M06-2X level in aqueous solution; also, to model the NADH-FUM reductase and analyze its intermolecular interactions by molecular docking. Quantum-chemical descriptors allowed to select the molecules with the best physicochemical properties and lowest toxicity. A high-quality three-dimensional structure of NADH-FUM reductase was obtained by homology modeling. Water molecules do not have influence in the interaction between FUM and NADH-FUM reductase. The main hydrogen-binding interactions for FUM were identified in NADH, Lys172, and Arg89; while hydrophobic interactions in Phe479, Thr174, Met63. The molecules S3-8, S2-8, and S1-8 could be inhibitors of NADH-FUM reductase.

Computational study of substituent effects on the acidity, toxicity and chemical reactivity of bacteriostatic sulfonamides.

Relationships among physicochemical properties, the chemical structure and antibacterial activity of sulfonamides have not been completely explicated yet. Nevertheless, from a therapeutics and prodrugs design point of view, a substituent group can modify the electronic structure, the physicochemical features and chemical reactivity which are critical for the biological activity. In this work, we analyze the substituent effects on the physicochemical properties, toxicity, chemical reactivity and its relation with the bacteriostatic activity of selected sulfonamides by means of DFT-M06-2X calculations in aqueous solution, using quantum chemical and docking descriptors. A correlation between the theoretical acidity and the pKa experimental values has been found. The more active sulfonamides have a larger acidity. The acidity increases with electron-withdrawing substituents. The main reactivity takes place on N4 atoms linked to aromatic ring, and in the SO2NH moiety, which are influenced by substituents. Docking descriptors showed binding affinities between sulfonamides and target receptor, the dihydropteroate synthase (DHPS).

Polymorphism, Intermolecular Interactions, and Spectroscopic Properties in Crystal Structures of Sulfonamides.

The antibiotics family of sulfonamides has been used worldwide intensively in human therapeutics and farm livestock during decades. Intermolecular interactions of these sulfamides are important to understand their bioactivity and biodegradation. These interactions are also responsible for their supramolecular structures. The intermolecular interactions in the crystal polymorphs of the sulfonamides, sulfamethoxypyridazine, and sulfamethoxydiazine, as models of sulfonamides, have been studied by using quantum mechanical calculations. Different conformations in the sulphonamide molecules have been detected in the crystal polymorphs. Several intermolecular patterns have been studied to understand the molecular packing behavior in these antibiotics. Strong intermolecular hydrogen bonds and π-π interactions are the main driving forces for crystal packing in these sulfonamides. Different stability between polymorphs can explain the experimental behavior of these crystal forms. The calculated infrared spectroscopy frequencies explain the main intermolecular interactions in these crystals.

Study of the Chemical Space of Selected Bacteriostatic Sulfonamides from an Information Theory Point of View.

The relative structural location of a selected group of 27 sulfonamide-like molecules in a chemical space defined by three information theory quantities (Shannon entropy, Fisher information, and disequilibrium) is discussed. This group is composed of 15 active bacteriostatic molecules, 11 theoretically designed ones, and para-aminobenzoic acid. This endeavor allows molecules that share common chemical properties through the molecular backbone, but with significant differences in the identity of the chemical substituents, which might result in bacteriostatic activity, to be structurally classified and characterized. This is performed by quantifying the structural changes on the electron density distribution due to different functional groups and number of electrons. The macroscopic molecular features are described by means of the entropy-like notions of spatial electronic delocalization, order, and uniformity. Hence, an information theory three-dimensional space (IT-3D) emerges that allows molecules with common properties to be gathered. This space witnesses the biological activity of the sulfonamides. Some structural aspects and information theory properties can be associated, as a result of the IT-3D chemical space, with the bacteriostatic activity of these molecules. Most interesting is that the active bacteriostatic molecules are more similar to para-aminobenzoic acid than to the theoretically designed analogues.

Predominant information quality scheme for the essential amino acids: an information-theoretical analysis.

In this work we undertake a pioneer information-theoretical analysis of 18 selected amino acids extracted from a natural protein, bacteriorhodopsin (1C3W). The conformational structures of each amino acid are analyzed by use of various quantum chemistry methodologies at high levels of theory: HF, M062X and CISD(Full). The Shannon entropy, Fisher information and disequilibrium are determined to grasp the spatial spreading features of delocalizability, order and uniformity of the optimized structures. These three entropic measures uniquely characterize all amino acids through a predominant information-theoretic quality scheme (PIQS), which gathers all chemical families by means of three major spreading features: delocalization, narrowness and uniformity. This scheme recognizes four major chemical families: aliphatic (delocalized), aromatic (delocalized), electro-attractive (narrowed) and tiny (uniform). All chemical families recognized by the existing energy-based classifications are embraced by this entropic scheme. Finally, novel chemical patterns are shown in the information planes associated with the PIQS entropic measures.

Insight into the informational-structure behavior of the Diels-Alder reaction of cyclopentadiene and maleic anhydride.

The course of the Diels-Alder reactions of cyclopentadiene and maleic anhydride were studied. Two reaction paths were modelled: endo- and exo-selective paths. All structures within the transient region were characterized and analyzed by means of geometrical descriptors, physicochemical parameters and information-theoretical measures in order to observe the linkage between chemical behavior and the carriage of information. We have shown that the information-theoretical characterization of the chemical course of the reaction is in complete agreement with its phenomenological behavior in passing from reactants to products. In addition, we were able to detect the main differences between the two reaction mechanisms. This type of informational analysis serves to provide tools to help understand the chemical reactivity of the two simplest Diels-Alder reactions, which permits the establishment of a connection between the quantum changes that molecular systems exert along reaction coordinates and standard physicochemical phenomenology. In the present study, we have shown that every reaction stage has a family of subsequent structures that are characterized not solely by their phenomenological behavior but also by informational properties of their electronic density distribution (localizability, order, uniformity). Moreover, we were able to describe the main differences between endo-adduct and exo-adduct pathways. With the advent of new experimental techniques, it is in principle possible to observe the structural changes in the transient regions of chemical reactions. Indeed, through this work we have provided the theoretical concepts needed to unveil the concurrent processes associated with chemical reactions.

Oxidation mechanism of methionine by HO• radical: a theoretical study.

A theoretical investigation at the MP2/6-311++G(2d,2p)//MP2/6-31+G(d,p) level was employed in order to study the one-electron oxidation mechanism of methionine in aqueous solution. Three reaction paths corresponding to the HO(•), O(2) attack and hydrolysis were considered. Results show that all the processes are exothermic and that the rate determining step can be associated with the hydrolysis reaction. DFT computations with different exchange-correlation potentials were performed in order to verify their reliability in the description of the cyclic adduct produced in the HO(•) attack step.

Electronic structure evaluation through quantum chemical descriptors of 17ß-aminoestrogens with an anticoagulant effect.

17ß-aminoestrogens have been experimentally studied due to their anticoagulant effect, shown both in in vitro and in vivo assays; this is a non-typical behavior for steroids. The anticoagulant effect of these aminoestrogens has been related to the aromaticity of the A-ring of the steroid molecule; as well as to the length of the amino-alcohol side-chain at C17, which might have an influence on the biological activity of these compounds. The study of the electronic structure of 17ß-aminoestrogens using quantum chemical descriptors could provide significant information and may contribute to a better understanding of structure-activity relationships in these molecules. In this work, we present a density functional theory (DFT) study at the B3LYP level of theory for selected 17ß-aminoestrogens compounds, with the main purpose of characterizing their electronic and physicochemical properties and relating them to their anticoagulant effect, using quantum chemical descriptors such as: atomic charges, bond order, electrostatic potential isosurface analysis, hardness, electrophilicity and aromaticity indexes. The results obtained from these quantum chemical descriptors, led us to characterize the physicochemical properties, reactive sites and substituent influence on electronic structure, as well as to identify additional quantum chemical descriptors that could be associated with the anticoagulant effect of 17ß-aminoestrogens.

Theoretical study of the competition between intramolecular hydrogen bonds and solvation in the Cys-Asn-Ser tripeptide.

A study of the competition between intra- and intermolecular hydrogen bonds and its influence on the stability of the Cys-Asn-Ser tripeptide in aqueous solution was performed by using the averaged solvent electrostatic potential from molecular dynamics method (ASEP/MD). The model combines a DFT-B3LYP/6-311+G(d) quantum treatment in the description of the solute molecule with NVT molecular dynamics simulations in the description of the solvent. In gas phase, the most stable structure adopts a C5 conformation. Somewhat higher in energy are found the PP(II) and C7eq structures. In solution, the stability order of the different conformers is reversed: the PP(II) structure becomes the most stable, and the C5 structure is strongly destabilized. The conformational equilibrium is shifted toward conformations in which the intramolecular hydrogen bonds (IHB) have been substituted with intermolecular hydrogen bonds with the water molecules. The solvent stabilizes extended structures without IHBs that are not stable in vacuum. The effect of the protonation state on the conformational equilibrium was also analyzed.

Computational study of the electronic structure characterization of a novel anti-inflammatory tripeptide derived from monocyte locomotion inhibitory factor (MLIF)-pentapeptide.

The structure and properties of molecules are determined by their charge-density distribution. Several works have shown that electron delocalization along the peptide backbone and side-chain modulates the physical and chemical features of peptides and protein properties. Research on Entamoeba histolytica-soluble factors led to the identification of the pentapeptide Met-Gln-Cys-Asn-Ser, with anti-inflammatory in vivo and in vitro effects. A synthetic pentapeptide, Met-Pro-Cys-Asn-Ser, maintained the same anti-inflammatory actions in experimental assays. A previous theoretical study allowed proposing the Cys-Asn-Ser tripeptide (CNS tripeptide) as the pharmacophore group of both molecules. This theoretical hypothesis was recently confirmed experimentally. The aim of this study was to characterize the electronic structure and physico-chemical properties of the CNS tripeptide through a theoretical study at the second-order Møller-Plesset perturbation theory (MP2) and density functional theory (DFT) theoretical levels. Our results in deprotonation energies show that the hydrogen atom (H2) of the serine-amide group possesses acidic characteristics. This result was confirmed by means of a study of bond order. Atomic charges, dipole moment, frontier molecular orbitals (Highest occupied molecular orbital [HOMO-1] and Lowest unoccupied molecular orbital [LUMO+1]), and electrostatic potential isosurface and its geometric parameters permitted to characterize its electronic structure and physico-chemical features and to identify some reactive sites that could be associated with this tripeptide's anti-inflammatory activity.

The Cys-Asn-Ser carboxyl-terminal end group is the pharmacophore of the amebic anti-inflammatory monocyte locomotion inhibitory factor (MLIF).

The monocyte locomotion inhibitory factor (MLIF) is an anti-inflammatory oligopeptide produced by Entamoeba histolytica. Among its different effects, it inhibits locomotion of human monocytes, hence its original name. Previous experimental studies have shown that the anti-inflammatory properties of MLIF (Met-Gln-Cys-Asn-Ser) remained when aminoacid glutamine was substituted by a proline in the second position (pMLIF: Met-Pro-Cys-Asn-Ser). By changing the order of MLIF amino acids, the resulting scrambled oligopeptide (sMLIF: Gln-Cys-Met-Ser-Asn) has failed activity. By means of ab initio study at the Hartree-Fock and Density Functional Theory levels, it was found that MLIF and pMLIF peptides maintain a great structural similarity among the last three amino acids (...Cys-Asn-Ser) predicting a pharmacophore. The objective of this work was to experimentally verify in vivo and in vitro the existence of the pharmacophore group in MLIF. We assayed three tripeptides by respiratory burst and delayed hypersensitivity skin reactions. The tripeptide Cys-Asn-Ser carboxyl-terminal end group maintained 100% of its biological properties, as well as the anti-inflammatory activity of MLIF, while the other tripeptides tested did not do that.

Electronic structure and physicochemical properties characterization of the amino acids 12-26 of TP53: a theoretical study.

PNC-27, a synthetic peptide, is derived from the TP53-HDM2 binding domain that include TP53 amino acids 12-26 linked with 17 amino acids from the antennapedia protein transference domain. This peptide induces membrane rupture in tumor cells through toroidal pores formation and has motivated several experimental studies; nonetheless, its mechanism of biological action remains unknown to date. Herein, we present a theoretical study at the Hartree-Fock and density functional theory (B3LYP) levels of theory of TP53 protein residues 12-26 (PPLSQETFSDLWKLL) in order to characterize its electronic structure and physicochemical properties. Our results for atomic and group charges, fitted to the electrostatic potential (ESP) show important reactive sites (L14, S15, T18, S20, L25, and L26), suggesting that these amino acids are exposed to nucleophilic and electrophilic attacks. Analysis of bond orders, intramolecular interactions and of several global reactivity descriptors, such as ionization potentials, hardness, electrophilicity index, dipole moments, total energies, frontier molecular orbitals (HOMO-LUMO), and electrostatic potential, led us to characterize active sites and the electronic structure and physiochemical features that taken together may be important in understanding the specific selectivity for this peptides type's cancer-cell membrane lysis properties.