Conformational fingerprints in the modelling performance of MIA-QSAR: a case for SARS-CoV protease inhibitors.

Multivariate image analysis applied to quantitative structure-activity relationships (MIA-QSAR) has proved to be a high-performance 2D tool for drug design purposes. Nonetheless, MIA-QSAR strategy does not efficiently incorporate conformational information. Therefore, understanding the implications of including this type of data into the MIA-QSAR model, in terms of predictability and interpretability, seems a crucial task. Conformational information was included considering the optimised geometries and the docked structures of a series of disulfide compounds potentially useful as SARS-CoV protease inhibitors. The traditional analysis (based on flat-shape molecules) proved itself as the most effective technique, which means that, despite the undeniable importance of conformation for biomolecular behaviour, this type of information did not bring relevant contributions for MIA-QSAR modelling. Consequently, promising drug candidates were proposed on the basis of MIA-plot analyses, which account for PLS regression coefficients and variable importance in projection scores of the MIA-QSAR model.

The Role of Intramolecular Interactions on the Bioactive Conformation of Epinephrine.

The structure of bioactive compounds inside their biological target is mainly dictated by the intermolecular interactions present in the binding side, whereas intramolecular interactions are responsible for the structure of an isolated molecule. Accordingly, this work reports the relative significance of these interactions for the bioactive conformation of the N-protonated epinephrine. The crystallized structure of epinephrine has a gauche orientation of the O-C-C-N torsion angle. Conformational analysis in the gas phase and implicit water was performed to investigate the main intramolecular forces favoring this conformational preference, which was primarily attributed to the electrostatic interaction between hydroxyl and ammonium groups. However, when the conformers were docked into the active site, intramolecular interactions were surpassed by intermolecular hydrogen bonds with neighboring amino acid residues. Nonetheless, structural modifications aiming at strengthening intramolecular interactions could be used to modulate a bioactive conformation, thereby assisting in the structure-based design of new chemical entities.

Morphology of the Diaphragm Muscle in Southern Tamandua (Tamandua tetradactyla) and its Importance in Cases of Traumatic Hernia.

The wall of the diaphragm can be affected by changes caused by physical trauma, allowing the passage of viscera between the abdominal cavity and thoracic cavity, thus reducing the space for pulmonary expansion, leading to the formation of hernia and possible death. Thus, we aimed to characterize, size and determine the topography of the diaphragmatic muscle in the Southern Tamandua, since clinical and surgical activities in wild animals have become a reality more and more present in veterinary medicine. We used six adult animals, x-rayed and dissected, followed by collection of fragments of muscular portions for histological analysis. Initially we observed that the animals presented 17 thoracic vertebrae, 3 lumbar vertebrae and 5 sacral vertebrae. The diaphragm was conformed by three segments: sternal, costal and right and left diaphragm pillar, with presence of tendinous centre that housed the passage of the caudal vena cava, called foramen of the caudal vena cava. Dorsally to the tendinous centre, already in the muscle portion, we located the esophageal and aortic hiatus. These findings, as well as the microscopic, were equivalent to that found in the general literature also, corroborating with descriptions already carried out in other mammals' diaphragms.

Impacto psicossocial e comportamental da alergia alimentar em crianças, adolescentes e seus familiares: uma revisão / Psychosocial and behavioral impact of food allergies on children, adolescents and their families: a review

Objetivo: Analisar as evidências da literatura sobre a relação entre alergia alimentar infantil e o impacto psicossocial e comportamental em crianças, adolescentes e seus familiares. Método: Realizou-se uma busca bibliográfica nas seguintes bases de dados: Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), National Center for Biotechnology Information (PubMed) e na biblioteca eletrônica Scientific Electronic Library On-line (SciELO), com foco em artigos publicados no período de 1995 a 2017, em português e/ou inglês. Os descritores utilizados foram: food allergy, children, anxiety, feeding disorders e quality of life. Resultados: A prevalência das doenças alérgicas tem aumentado nas últimas décadas, sobretudo entre as crianças, com impacto significativo sobre os aspectos da vida diária e qualidade de vida tanto da criança quanto da família. Ansiedade, faltas escolares e bullying têm maior incidência em crianças com alergia alimentar. Quanto aos cuidadores, há maior prevalência de estresse, depressão e isolamento por medo de exposição a alérgenos. Conclusão: É possível verificar uma relação entre alergias alimentares em crianças e uma piora da qualidade de vida. Ademais, as dificuldades alimentares advindas de alergias (motoras, neofobias e preferências alimentares) podem prejudicar o desenvolvimento e crescimento das crianças. É necessário o acompanhamento por equipe multiprofissional especializada e treinada, além de mais estudos que abordem novas estratégias e técnicas específicas para o tratamento desta população.

Objective: To analyze evidence available in the literature on the relationship between food allergies in children and their psychosocial and behavioral impact on the patients (children or adolescents) and their families. Method: A literature search was conducted in the following databases: Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS), National Center for Biotechnology Information (PubMed), and Scientific Electronic Library Online (SciELO), browsing for articles published between 1995 and 2017, in Portuguese and/or English. The following descriptors were used: food allergy, children, anxiety, feeding disorders, and quality of life. Results: The prevalence of allergic diseases has increased over the past few decades, especially among children, with significant impact on daily living and quality of life of both the child and the family. Anxiety, school absenteeism and bullying have higher incidence rates in children with food allergies. Among caregivers, higher prevalence rates of stress, depression and isolation for fear of exposure to allergens were observed. Conclusion: It is possible to identify a relationship between food allergies in children and worse quality of life. Furthermore, the difficulties resulting from food allergies (motor skills, food neophobia and food preferences) may affect the children's development and growth. Follow-up by a specialized, trained multidisciplinary team is required, as are further studies addressing new strategies and techniques specifically designed for the treatment of this population.

Theoretical Study on the Conformational Bioeffect of the Fluorination of Acetylcholine.

There has been an increasing interest in the study of fluorinated derivatives of gamma-aminobutyric acid (GABA), an acetylcholine (AC) analog. This work reports a theoretical study on the effect of an α-carbonyl fluorination in AC, aiming at understanding the role of a distant fluorine relative to the positively charged nitrogen on the conformational folding of the resulting fluorinated AC. In addition, the chemical and structural changes were evaluated on the basis of ligand-enzyme (acetylcholinesterase) interactions. In an enzyme-free environment, the fluorination yields conformational changes relative to AC due to the appearance of some attractive interactions with fluorine and a weaker steric repulsion between the fluorine substituent and the carboxyl group, rather than to a possible electrostatic interaction F⋅⋅⋅N+ . Moreover, the gauche orientation in the N-C-C-O fragment of AC owing to the electrostatic gauche effect is reinforced after fluorination. For instance, the conformational equilibrium in AC is described by a competition between gauche and anti conformers (accounting for the N-C-C-O dihedral angle) in DMSO, while the population for a gauche conformer in the fluorinated AC is almost 100 % in both gas phase and DMSO. However, this arrangement is disrupted in the biological environment even in the fluorinated derivative (whose bioconformation-like geometry shows a ligand-protein interaction of -84.1 kcal mol-1 against -79.5 kcal mol-1 for the most stable enzyme-free conformation), which shows an anti N-C-C-O orientation, because the enzyme induced-fit takes place. Nevertheless, the most likely bioconformation for the fluorinated AC does not match the bioactive AC backbone nor the most stable enzyme-free conformation, thus revealing the role of fluorination on the bioconformational control of AC.

Computational enzymology for degradation of chemical warfare agents: promising technologies for remediation processes.

Chemical weapons are a major worldwide problem, since they are inexpensive, easy to produce on a large scale and difficult to detect and control. Among the chemical warfare agents, we can highlight the organophosphorus compounds (OP), which contain the phosphorus element and that have a large number of applications. They affect the central nervous system and can lead to death, so there are a lot of works in order to design new effective antidotes for the intoxication caused by them. The standard treatment includes the use of an anticholinergic combined to a central nervous system depressor and an oxime. Oximes are compounds that reactivate Acetylcholinesterase (AChE), a regulatory enzyme responsible for the transmission of nerve impulses, which is one of the molecular targets most vulnerable to neurotoxic agents. Increasingly, enzymatic treatment becomes a promising alternative; therefore, other enzymes have been studied for the OP degradation function, such as phosphotriesterase (PTE) from bacteria, human serum paraoxonase 1 (HssPON1) and diisopropyl fluorophosphatase (DFPase) that showed significant performances in OP detoxification. The understanding of mechanisms by which enzymes act is of extreme importance for the projection of antidotes for warfare agents, and computational chemistry comes to aid and reduce the time and costs of the process. Molecular Docking, Molecular Dynamics and QM/MM (quantum-mechanics/molecular-mechanics) are techniques used to investigate the molecular interactions between ligands and proteins.

Computational Enzymology and Organophosphorus Degrading Enzymes: Promising Approaches Toward Remediation Technologies of Warfare Agents and Pesticides.

The re-emergence of chemical weapons as a global threat in hands of terrorist groups, together with an increasing number of pesticides intoxications and environmental contaminations worldwide, has called the attention of the scientific community for the need of improvement in the technologies for detoxification of organophosphorus (OP) compounds. A compelling strategy is the use of bioremediation by enzymes that are able to hydrolyze these molecules to harmless chemical species. Several enzymes have been studied and engineered for this purpose. However, their mechanisms of action are not well understood. Theoretical investigations may help elucidate important aspects of these mechanisms and help in the development of more efficient bio-remediators. In this review, we point out the major contributions of computational methodologies applied to enzyme based detoxification of OPs. Furthermore, we highlight the use of PTE, PON, DFP, and BuChE as enzymes used in OP detoxification process and how computational tools such as molecular docking, molecular dynamics simulations and combined quantum mechanical/molecular mechanics have and will continue to contribute to this very important area of research.

QSAR analysis of nicotinamidic compounds and design of potential Bruton's tyrosine kinase (Btk) inhibitors.

Bruton's tyrosine kinase (Btk) is an important enzyme in B-lymphocyte development and differentiation. Furthermore, Btk expression is considered essential for the proliferation and survival of these cells. Btk inhibition has become an attractive strategy for treating autoimmune diseases, B-cell leukemia, and lymphomas. With the objective of proposing new candidates for Btk inhibitors, we applied receptor-dependent four-dimensional quantitative structure-activity relationship (QSAR) methodology to a series of 96 nicotinamide analogs useful as Btk modulators. The QSAR models were developed using 71 compounds, the training set, and externally validated using 25 compounds, the test set. The conformations obtained by molecular dynamics simulation were overlapped in a virtual three-dimensional cubic box comprised of 2 and 5 Å cells, according to the six trial alignments. The models were generated by combining genetic function approximation and partial least squares regression technique. The analyses suggest that Model 1a yields the best results. The best equation shows [Formula: see text], r(2) = .743, RMSEC = .831, RMSECV = .879. Given the importance of the Tyr551, this residue could become a strategic target for the design of novel Btk inhibitors with improved potency. In addition, the good potency predicted for the proposed M2 compound indicates this compound as a potential Btk inhibitor candidate.