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Aim: Assess the in vitro effect of hepatitis B virus (HBV) genotype H (HBV/H) with the small surface HBV protein (HBs) C107R mutation on hepatitis B surface antigen (HBsAg) detection, TGFB1, CAT and IFNB1A expression, and the response to IFN-β-1a treatment. Methods: HBV/H wild-type and HBs C107R variant replicons were constructed and transfected into hepatic stellate cells and/or Huh7 that were later treated with IFN-β-1a. HBsAg, HBV-DNA, pgRNA, TGFB1, CAT and IFNB1A expression was analyzed. 3D HBs structure from wild-type and C107R were foreseen by AlphaFold protein predictor, and IFN-β-1a antiviral effect was evaluated. Results: C107R mutation did not impact viral replication, but HBsAg serologic detection was affected. Wild-type and C107R similarly modified gene expression and responded to IFN-β-1a. Conclusion: C107R disrupts the Cys107/Cys138 disulfide bond and impairs HBsAg detection. Independently of the mutation, there were changes in TGFB1, CAT and IFNB1A expression, and a medium response to IFN-β-1a treatment compared with genotype A and C.

Cancer is the second cause of death worldwide, leading to the high mortality rate, breast cancer. It is a global health problem due to its severe clinical manifestations and it is also related to a great variety of genetic and environmental risk factors with which it is associated. The knowledge of molecules involved in tumor processes allows identifying therapeutic targets to develop new drugs. Computational chemistry allows exploring and analyzing molecules at the atomic level with therapeutic functionality. In this work, we evaluate and analyze the stability, the physicochemical properties and chemical reactivity of p53-derived peptides with cytotoxic effect on breast cancer, using quantum-chemical descriptors: chemical hardness, ionization potential, electrophilicity index, atomic charges, and molecular orbitals at the DFT-B3LYP level in aqueous solution, and its intermolecular interactions by molecular docking. The results showed that hydrophobic amino acids improve the cytotoxic effect. Peptides with three mutations are less stable than peptides with two mutations; hence, a more stable peptide does not necessarily imply a high therapeutic effect. Residues: F19, W22, W23 and their respective atomic charges of nitrogen atoms, and its hydrogens (NH) of the amide groups of these amino acids are determinants for the interactions, also contribute to the stability and chemical reactivity and consequently, to the binding affinity of p53 derivative peptides with MDM2 protein.

Neglected tropical diseases caused by parasitic pathogens have caused an increase in research interest in drug discovery. Chagas disease is caused by protozoan Trypanosoma cruzi. Benznidazole and nifurtimox are effective drugs in the acute phase; nevertheless, for long-time treatment, they are toxic and have side effects, because these molecules produce free radicals and suffer oxidation–reduction processes. Studies of the structure and mode of action of these drugs have been performed and, until today, no effective treatment for this disease has been established yet. DFT-M06-2X studies in solution allowed us to explore the substituent effects on stability energy, physicochemical properties and chemical reactivity of nitroimidazoles with potential antiparasitic effects, using quantum-chemical descriptors: proton affinities, substituent effect stabilization energy, ionization potential, electrophilicity, hardness, atomic charges, dipole moment and Fukui functions. The basicity of the N3 atom and dipole moment decrease while the ionization potential, electrophilicity, and hardness increase with the electron-withdrawing substituents. Atomic charges, Fukui functions, and electrostatic potential showed that the main reactivity was on the nitro group and N3 atom. The methyl group linked to C2, and the position and inductive effect caused by the nitro group provoked major changes in the physicochemical features, chemical reactivity, and geometrical and energetic stabilities. Quantum-chemical descriptors allowed us to analyze and design novel nitroimidazole derivatives.

Se probó el efecto del quitosano sobre la producción de metabolitos secundarios de extractos etanólicos de Piper auritum, así como la actividad fungicida in vitro contra Fusarium oxysporum f. sp. vanillae. Las plantas de P. auritum se dividieron en seis parcelas y se añadió quitosano comercial a la mitad de ellas. Se midieron las concentraciones de flavonoides, fenoles, terpenos, alcaloides y ácido salicílico en extractos etanólicos de P. auritum y la actividad antifúngica se midió con la concentración efectiva media (CE50). Las concentraciones totales de flavonoides, fenoles y terpenos fueron más altas con el tratamiento con quitosano (sin quitosano 12.8 versus con quitosano 12.4 ?g equivalente de quercetina por mg, 12.6 versus 2.3 ?g equivalente de ácido tánico por 10 mg y 16.3 versus 11.6 mg equivalente de mentol por 100 mg). Mientras que la concentración de alcaloides disminuyó mediante la adición de quitosano (de 148.2 a 84.5 ?g de equivalente de piperina por mg). La adición de quitosano aumentó la concentración de ácido salicílico (de 1.3 a 2.2 ?g de equivalente de ácido salicílico por mg). La concentración de 4 mg mL-1 de extracto etanólico de P. auritum tratado con quitosano inhibió el 100% del crecimiento micelial. El tratamiento con quitosano generó que la CE50 de P. auritum contra F. oxysporum f. sp. vanillae fuera menor (1.5 mg mL-1) respecto al control (5.1 mg mL-1). Se concluye que la adición de quitosano aumentó la producción de metabolitos secundarios y la actividad antifúngica in vitro en extractos de P. auritum.

There is a growing interest to study and address neglected tropical diseases (NTD). To this end, in silico methods can serve as the bridge that connects academy and industry, encouraging the development of future treatments against these diseases. This chapter discusses current challenges in the development of new therapies, available computational methods and successful cases in computer-aided design with particular focus on human trypanosomiasis. Novel targets are also discussed. As a case study, we identify amentoflavone as a potential inhibitor of TcSir2rp3 (sirtuine) from Trypanosoma cruzi (20.03 μM) with a workflow that integrates chemoinformatic approaches, molecular modeling, and theoretical affinity calculations, as well as in vitro assays.

American Trypanosomiasis is a disease caused by the protozoan parasite Trypanosoma cruzi agent. Nifurtimox and benznidazole are effective drugs in the acute phase; however, are toxic and have adverse effects. Nonetheless, the nitroheterocycles are good models to design other compounds with less side effects. Theoretical and experimental studies have been performed about the structure and mode action of these drugs and at present, no effective treatment of this disease has been established yet, and the parasitic infections increase each year. The aim of this work, was to analyze the substituent effects on the physicochemical properties and chemical reactivity of selected antiparasitic 5-nitrofurans, using quantum-chemical descriptors: acidity, proton affinities, SESE, potential ionization, hardness, electrophilicity, aromaticity, dipole moment and Fukui functions at the DFT-M06-2X level in aqueous solution. The acidity of the azomethine group increases with the presence of the electron-withdrawing groups. The electron-donating groups favor the basicity and the energy of stabilization in the active molecule (NFX). The atomic charges, the quantum chemical descriptors and Fukui function ( f k + ) showed that the main reactivity takes place on the Ar-NO2. These results reinforce the importance of the nitro group in the redox processes of the 5-nitrofurans that are involved in the trypanocidal effect.

The genus Leptospira encompass 22 species of spirochaetes, with ten pathogenic species that have been recorded in more than 160 mammals worldwide. In the last two decades, the numbers of records of these agents associated with bats have increased exponentially, particularly in America. Although order Chiroptera represents the second most diverse order of mammals in Mexico, and leptospirosis represents a human and veterinary problem in the country, few studies have been conducted to identify potential wildlife reservoirs. The aim of this study was to detect the presence and diversity of Leptospira sp. in communities of bats in an endemic state of leptospirosis in Mexico. During January to September 2016, 81 bats of ten species from three localities of Veracruz, Mexico, were collected with mist nets. Kidney samples were obtained from all specimens. For the detection of Leptospira sp., we amplified several genes using specific primers. Amplicons of the expected size were submitted to sequencing, and sequences recovered were compared with those of reference deposited in GenBank using the BLAST tool. To identify their phylogenetic position, we realized a reconstruction using maximum-likelihood (ML) method. Twenty-five samples from three bat species (Artibeus lituratus, Choeroniscus godmani and Desmodus rotundus) showed the presence of Leptospira DNA. Sequences recovered were close to Leptospira noguchii, Leptospira weilii and Leptospira interrogans. Our results include the first record of Leptospira in bats from Mexico and exhibit a high diversity of these pathogens circulating in the state. Due to the finding of a large number of positive wild animals, it is necessary to implement a surveillance system in populations of the positive bats as well as in related species, in order to understand their role as carriers of this bacterial genus.

We aimed to determine the seroprevalence of infection with Neospora caninum, Leptospira, and bovine herpesvirus type 1 and risk factors associated with these infections in water buffaloes in Veracruz State, Mexico. Through a cross-sectional study, 144 water buffaloes (Bubalus bubalis) raised in 5 ranches of Veracruz were examined for anti-N. caninum and anti-bovine herpesvirus type 1 antibodies by enzyme immunoassays, and anti-Leptospira interrogans antibodies by microscopic agglutination test. Of the 144 buffaloes studied, 35 (24.3%) were positive for N. caninum, 50 (34.7%) for Leptospira, and 83 (57.6%) for bovine herpes virus. The frequencies of leptospiral serovars in buffaloes were as follows: 18.7% for Muenchen (n = 27), 10.4% for Hardjo LT (n = 15), 9.0% for Pyrogenes (n = 13), and 4.8% for Icterohaemorrhagiae (n = 7). Seropositive buffaloes were found in all 5 ranches studied. Logistic regression showed that cohabitation of buffaloes with cows was associated with infection with Leptospira (odds ratio [OR], 2.2; 95% confidence interval [CI], 1.04–4.5; P = 0.03) and bovine herpesvirus (OR, 12.0; 95% CI, 4.0–36.2; P < 0.01). This is the first study that provides serological evidence of N. caninum, Leptospira, and bovine herpesvirus type 1 infections in water buffaloes in Mexico. Our findings could be used to enhance preventive measures against these infections.

El colesterol es un esteroide de origen animal que cumple numerosas funciones metabólicas, es un precursor de ácidos biliares, de los esteroles fecales, de la vitamina D y de las hormonas esteroideas. Este esteroide es sintetizado en el hígado y otros tejidos, y puede ser absorbido a través de alimentos que se encuentran en nuestra dieta. Tiene una doble ligadura susceptible de oxidarse formando oxiesteroles. No obstante que se encuentran en pequeñas concentraciones son moléculas versátiles porque participan en diversas funciones metabólicas, favorecen algunas patologías ó regulan la expresión de los genes. La intervención de los oxiesteroles en la aterosclerosis es la patología más estudiada, aunque también se ha estudiado su participación en enfermedades neurodegenerativas como el Alzheimer. A partir de la manipulación genética in vivo, así como el uso de simulaciones por ordenadores, se podrá comprender cómo los oxiesteroles gobiernan la señalización celular, modulan la expresión génica, e influyen en nuestra salud o enfermedad.Palabras clave: Colesterol; esteroide; oxiesteroles; aterosclerosis; Alzheimer AbstractCholesterol is a steroid of animal origin that meets numerous metabolic functions, is a pre­cursor of bile acids, fecal sterols, vitamin D and steroid hormones. This steroid is synthesized in the liver and other tissues, and can be absorbed through foods that are found in our diet. It has a double ligature susceptible to oxidizing forming oxysterols. Nevertheless they are found in slight concentrations are versatile molecules because they participate in diverse metabolic functions, they advantage some pathologies or they regulate the expression of the genes. The intervention of oxysterols in atherosclerosis is the most studied pathology, although its parti­cipation in neurodegenerative diseases such as Alzheimer’s has also been studied. So that the novel analytical tools will promote the study of oxysterols health or illness.Keywords: Cholesterol, steroid, oxysterols, atherosclerosis, Alzheimer

Inflammatory response events are initiated by a complex series of molecular reactions that generate chemical intermediaries. The structure and properties of peptides and proteins are determined by the charge distribution of their side chains, which play an essential role in its electronic structure and physicochemical properties, hence on its biological functionality. The aim of this study was to analyze the effect of changing one central amino acid, such as substituting asparagine for aspartic acid, from Cys–Asn–Ser in aqueous solution, by assessing the conformational stability, physicochemical properties, chemical reactivity and their relationship with anti-inflammatory activity; employing quantum-chemical descriptors at the M06-2X/6-311+G(d,p) level. Our results suggest that asparagine plays a more critical role than aspartic acid in the structural stability, physicochemical features, and chemical reactivity of these tripeptides. Substituent groups in the side chain cause significant changes on the conformational stability and chemical reactivity, and consequently on their anti-inflammatory activity.

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.

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).

Activity of steroid hormones is dependent upon a number of factors, as solubility, transport and metabolism. The functional differences caused by structural modifications could exert an influence on the chemical reactivity and biological effect. The goal of this work is to study the influence of the physicochemical and aromatic properties on the chemical reactivity and its relation with the carcinogenic risk that can associate with the anticoagulant effect of 17β-aminoestrogens using quantum-chemical descriptors at the DFT-B3LYP, BH&HLYP and M06-2X levels. The relative acidity of (H1) of the hydroxyl group increases with electron-withdrawing groups. Electron-donor groups favor the basicity. The steric hindrance of the substituents decreases the aromatic character and consequently diminution the carcinogenic effect. Density descriptors: hardness, electrophilic index, atomic charges, molecular orbitals, electrostatic potential and their geometric parameters permit analyses of the chemical reactivity and physicochemical features and to identify some reactive sites of 17β-aminoestrogens.

17β-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 17β-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 17β-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 17β-aminoestrogens.

Disulfide C-terminal loop fragments derived from AMPs and the presence of peptidases have been previously reported in the skin secretions of different amphibians. However, there are only a few studies on the identification of enzymes in frog skin secretion based on the primary structure of these proteins. Similarly, little data exist regarding the identification of disulfide C-terminal loops at large scale. Therefore, a comprehensive study on this issue certainly could bring in much more information for understanding this molecular process and its biochemical consequences. Thus, the aim of this work was to characterize the presence of disulfide C-terminal loop fragments of AMPs and identify the proteins and probable enzymes present in the completely unknown secretion contents of the frog Lithobates spectabilis. For this purpose, high-resolution mass spectrometry was applied to analyze the skin secretions processed by two different protocols: (1) using a cocktail of enzymatic inhibitors and 2) without any protease inhibitors, maintaining the solution for 2 hours at 10°C. Results from procedure-1, revealed 122 molecular masses, whereas procedure-2 permitted 253 different molecular masses to be identified. Fifty-nine peptides including 22 disulfide C-terminal loop-containing peptides were obtained following procedure-2. Polyacrylamide gel electrophoresis separation, tryptic digestion and LCMS/ MS were used for "de novo" sequencing of 111 different peptides and the unequivocal identification of fifteen proteins including at least three different peptidases. Additionally, it was possible to fully sequence eight peptides, including a ranatuerin-related peptide identified here as Spectabilin, that was subsequently chemically synthesized and showed high antibacterial, antiparasitic and cytotoxic activities.

Pediatric patients with malignant gliomas and same histological diagnosis respond distinctly to treatment. It is thus necessary to determine other factors that may influence the response to treatment and survival. Over expression of the Ki67 protein has been associated with poor treatment response. The aim of this study was to determine if the expression of this antigen influences survival of patients treated for malignant gliomas in the CMN SXXI Pediatrics Hospital.We included patients with anaplasic astrocitoma or glioblastoma multiforme seen at our hospital between 1995 and 2005. We determined the expression of Ki67 by immunohistochemistry and correlated the findings with tumor histology and patient survival.Of the 21 patients studied, 12 overexpressed antigen Ki67. There was no significant association between over expression of Ki67 and survival, although we observed a clinical association. Over expression of Ki67 correlated with more aggressive histology. Being under the age of 11 was a poor prognostic factor. Overall survival was 49% at 120 months.Being young (under 11 years) is a marker of poor prognosis among pediatric patients with anaplasic astrocytoma or glioblastoma multiforme. Overexpression expression of antigen Ki67 is associated with histology and may be associated with poor survival among patients treated in our hospital.

It has been discussed in the literature that electron delocalization along the peptide backbone and side chain modulates the physical and chemical features of peptides and proteins. The structure and properties of peptides are determined by their charge-density distribution, such that the modification of its side chain plays an important role on its electronic structure and physicochemical 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 objective of this work was to study the influence of the electron donor and electron withdrawing substituent groups on the electronic structure and physicochemical properties of the CNS tripeptide derivatives through a theoretical study at the density functional theory level of theory. Our results in deprotonation energies showed that the relative acidity of hydrogen atom (H2) of the serine-amide group increases with the electron withdrawing groups. This result was confirmed by means of a study of bond order. The proton affinities illustrated that the electron donor groups favored the basicity of the amino group of the cysteine amino acid. Atomic charges, Frontier molecular orbitals (HOMO–LUMO), and electrostatic potential isosurface and its geometric parameters permitted to analyze the effect that provoked the electron donor and electron attractor groups on its electronic structure and physicochemical features and to identify some reactive sites that could be associated with the anti-inflammatory activity of tripeptide CNS derivatives. © 2010 Wiley Periodicals, Inc. Int J Quantum Chem 110:2398–2410, 2010

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 Moller–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.

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.