IN SILICO METHODS FOR DRUG DESIGN AND DISCOVERY

Computer-aided drug design (CADD) methodologies are playing an ever-increasing role in drug discovery that are critical in the cost-effective identification of promising drug candidates. These computational methods are relevant in limiting the use of animal models in pharmacological research, for aiding the rational design of novel and safe drug candidates, and for repositioning marketed drugs, supporting medicinal chemists and pharmacologists during the drug discovery trajectory.Within this field of research, we launched a Research Topic in Frontiers in Chemistry in March 2019 entitled “In silico Methods for Drug Design and Discovery,” which involved two sections of the journal: Medicinal and Pharmaceutical Chemistry and Theoretical and Computational Chemistry. For the reasons mentioned, this Research Topic attracted the attention of scientists and received a large number of submitted manuscripts. Among them 27 Original Research articles, five Review articles, and two Perspective articles have been published within the Research Topic. The Original Research articles cover most of the topics in CADD, reporting advanced in silico methods in drug discovery, while the Review articles offer a point of view of some computer-driven techniques applied to drug research. Finally, the Perspective articles provide a vision of specific computational approaches with an outlook in the modern era of CADD

Desenvolvimento de um modelo para avaliar o nível de manutenção Lean de uma organização : caso de estudo

Trabalho final de mestrado para obtenção do grau de mestre em Engenharia MecânicaA criação de um modelo de avaliação Lean é importante para criar boas práticas a aplicar na área da manutenção, como principio de uma atividade que utiliza ferramentas Lean e consciente de todas as suas vantagens. A implementação de filosofia Lean na manutenção visa melhorar o planeamento e a programação das atividades, aumentar a produtividade, motivar os trabalhadores, ajudar na introdução de novos hábitos e de novas atitudes no trabalho e ainda identificar os desperdícios que devem ser eliminados. A competitividade e o preço excessivo dos produtos (bens ou serviços) que o cliente final não quer pagar, faz com que as empresas públicas e privadas tomem medidas para evitar todo o tipo de desperdícios, rentabilizando ao máximo a sua cadeia de valor. A filosofia Lean foi uma das formas encontradas para identificar e eliminar alguns desses desperdícios, melhorando o processo produtivo e, desta forma, tornando as organizações mais competitivas. O Lean tem várias ferramentas podendo ser aplicadas em diversas áreas. Uma dessas áreas é a manutenção, onde se pretende que os equipamentos operem sem interrupções e com uma produção de qualidade. Algumas das ferramentas do Lean encaixam-se perfeitamente na área da manutenção para identificação de desperdícios, criação de valor, realização de planeamento, melhoria do sistema de trabalho na organização e até no próprio desenvolvimento dos trabalhadores. A presente dissertação visa mostrar algumas das ferramentas mais comuns da filosofia Lean com aplicabilidade na manutenção de equipamentos de apoio à atividade de um serviço publico e ao desenvolvimento de um modelo de avaliação com apresentação através de estudo de caso. No trabalho infra são apresentadas diversas ferramentas Lean, nomeadamente 5s, trabalho padronizado, (standardwork uniformização), gestão visual (andon), melhoria continua (kaisen), mapeamento fluxo de valor na manutenção (MVSM), SIPOC, gestão visual, 5w, ciclo PDCA. O modelo de avaliação está estruturado em 3 grandes áreas “Clientes”, “Organização” e “Fornecedores”, vai subdividir-se em 7 critérios e 60 atributos. Dos 60 atributos, foram desenvolvidos 6 e que compõem mais de 70 atributos, perfazendo mais de 130 no final o modelo proposto neste trabalho.The creation of a lean evaluation model is important to create good practice in the field of maintenance as the principle of an activity that uses lean tools aware of all its advantages. Implementing Lean's philosophy of maintenance aims to improve planning and scheduling of activities, increase productivity, motivate employees, assist in introducing new habits and new attitudes at work, and identify the wastes that need to be eliminated. Competitiveness and the excessive price of products (goods or services) that the final customer does not want to pay, makes public and private companies take measures to avoid all types of waste, making the most of its value chain. The Lean philosophy was one of the ways found to identify and eliminate some of these wastes, improving the production process and thus making companies more competitive. Lean has several tools that can be applied in several areas. One of these areas is maintenance, where the equipment is intended to operate without interruption and with a quality production. Some of Lean's tools fit perfectly into the maintenance area for waste identification, value creation. The present dissertation aims to show some of the most common tools of the Lean philosophy with applicability in the maintenance of equipment to support the activity of a public service and the development of an evaluation model with presentation through case study. In the work below are presented several Lean tools, namely 5s, standardized work, (standardwork standardization), visual management (andon), continuous improvement (kaisen), maintenance value flow mapping (MVSM), SIPOC, visual management, 5w, cycle PDCA. The avaliation model is structured in 3 large areas "Customers", "Organization" and "Suppliers", will be subdivided into 7 criteria and 60 attributes. Of the 60 attributes were developed 6 and that make up more than 70 attribute attributes, preferring more than 130 at the end the model proposeN/

Employing conformational analysis in the molecular modeling of agrochemicals: insights on QSAR parameters of 2,4-D

A common practice to compute ligand conformations of compounds with various degrees of freedom to be used in molecular modeling (QSAR and docking studies) is to perform a conformational distribution based on repeated random sampling, such as Monte-Carlo methods. Further calculations are often required. This short review describes some methods used for conformational analysis and the implications of using selected conformations in QSAR. A case study is developed for 2,4-dichlorophenoxyacetic acid (2,4-D), a widely used herbicide which binds to TIR1 ubiquitin ligase enzyme. The use of such an approach and semi-empirical calculations did not achieve all possible minima for 2,4-D. In addition, the conformations and respective energies obtained by the semi-empirical AM1 method do not match the calculated trends obtained by a high level DFT method. Similar findings were obtained for the carboxylate anion, which is the bioactive form. Finally, the crystal bioactive structure of 2,4-D was not found as a minimum when using Monte-Carlo/AM1 and is similarly populated with another conformer in implicit water solution according to optimization at the B3LYP/aug-cc-pVDZ level. Therefore, quantitative structure-activity relationship (QSAR) methods based on three dimensional chemical structures are not fundamental to provide predictive models for 2,4-D congeners as TIR1 ubiquitin ligase ligands, since they do not necessarily reflect the bioactive conformation of this molecule. This probably extends to other systems

Structural Parameters of the Interaction between Ciprofloxacin and Human Topoisomerase-II β Enzyme: Toward New ¹⁹F NMR Chemical Shift Probes

New tools for cancer diagnosis are being studied since early diagnosis can be crucial for a successful treatment. In this context, the use of NMR probes constitutes an efficient method of diagnosis. In this study, we investigated the use of ciprofloxacin to indirectly label the overexpression of topoisomerase-II enzymes by changes in 19F NMR chemical shifts of ciprofloxacin. Increased topoisomerase-II expression has been associated with cancer occurrence, mainly with aggressive forms of breast cancer, thus constituting a promising molecular target for new tumor cell identifiers. Using DFT calculations, we performed a spectroscopy analysis of ciprofloxacin in different chemical environments and evaluated the solvent and enzymatic effects. Our results show that ciprofloxacin forms a stable complex with the enzyme, and the main intermolecular interactions between ciprofloxacin and human topoisomerase-IIβ are hydrogen bonds, followed by π-π stacking and electrostatic interactions. Additionally, a shift of 6.04 ppm occurs in the 19F NMR signal when ciprofloxacin interacts with the human topoisomerase-IIβ enzyme, and this parameter may be an indirect marker indicating the overexpression of these enzymes in the body

Structural Parameters of the Interaction between Ciprofloxacin and Human Topoisomerase-II β Enzyme: Toward New 19F NMR Chemical Shift Probes

New tools for cancer diagnosis are being studied since early diagnosis can be crucial for a successful treatment. In this context, the use of NMR probes constitutes an efficient method of diagnosis. In this study, we investigated the use of ciprofloxacin to indirectly label the overexpression of topoisomerase-II enzymes by changes in 19F NMR chemical shifts of ciprofloxacin. Increased topoisomerase-II expression has been associated with cancer occurrence, mainly with aggressive forms of breast cancer, thus constituting a promising molecular target for new tumor cell identifiers. Using DFT calculations, we performed a spectroscopy analysis of ciprofloxacin in different chemical environments and evaluated the solvent and enzymatic effects. Our results show that ciprofloxacin forms a stable complex with the enzyme, and the main intermolecular interactions between ciprofloxacin and human topoisomerase-IIβ are hydrogen bonds, followed by π-π stacking and electrostatic interactions. Additionally, a shift of 6.04 ppm occurs in the 19F NMR signal when ciprofloxacin interacts with the human topoisomerase-IIβ enzyme, and this parameter may be an indirect marker indicating the overexpression of these enzymes in the body

Enzimas degradantes de organofosforados: Base molecular e perspectivas para biorremediação enzimática de agroquímicos

RESUMO Muitos compostos organofosforados (OP) são utilizados até hoje na agricultura como pesticidas e, infelizmente, como agentes de guerra química (ou agentes dos nervos) também. Os pesticidas organofosforados e os agentes dos nervos são moléculas extremamente tóxicas, uma vez que atuam como inibidores da enzima Acetilcolinesterase (AChE). O efeito mais preocupante da exposição a estes compostos é a toxicidade colinérgica aguda, ou seja, a perda de coordenação muscular. Uma vez que o indivíduo se contamina, o processo de intoxicação começa através da ligação do OP no sítio ativo da enzima AChE inativando-a. Os tratamentos atuais para pessoas expostas a baixas doses de OP podem ser realizados com atropina, oximas e benzodiazepínicos. Processos de remediação importantes envolvem o emprego de técnicas de biorremediação utilizando diferentes enzimas degradantes, como a Fosfotriesterase da Agrobacterium radiobacter e SMP-30. Devido ao elevado número de intoxicações anualmente, é crucial buscar métodos de tratamento mais potentes e eficazes, e nesta linha, as técnicas envolvendo biorremediação parecem ser bastante promissoras para este propósito

99Tc NMR as a promising technique for structural investigation of biomolecules : theoretical studies on the solvent and thermal effects of phenylbenzothiazole complex.

The phenylbenzothiazole compounds show antitumor properties and are highly selective. In this paper, the 99Tc chemical shifts based on the (99mTc)(CO)3(NNO) complex conjugated to the antitumor agent 2-(4′-aminophenyl)benzothiazole are reported. Thermal and solvent effects were studied computationally by quantum-chemical methods, using the density functional theory (DFT) (DFT level BPW91/aug-cc-pVTZ for the Tc and BPW91/IGLO-II for the other atoms) to compute the NMR parameters for the complex. We have calculated the 99Tc NMR chemical shifts of the complex in gas phase and solution using different solvation models (polarizable continuum model and explicit solvation). To evaluate the thermal effect, molecular dynamics simulations were carried, using the atom-centered density matrix propagation method at the DFT level (BP86/ LanL2dz). The results highlight that the 99Tc NMR spectroscopy can be a promising technique for structural investigation of biomolecules, at the molecular level, in different environments

Organophosphorus degrading enzymes: Molecular basis and perspectives for enzymatic bioremediation of agrochemicals

<p></p><p>ABSTRACT Many organophosphorus compounds (OP) are used until today in agriculture as pesticides and, unfortunately, they are used as chemical warfare agents (or nerve agents) as well. Organophosphorus pesticides and nerve agents are extremely toxic molecules, since they act as Acetylcholinesterase (AChE) inhibitors. The most worrying effect of the exposure to these compounds is the acute cholinergic toxicity, which is the loss of muscle coordination. Once one is contaminated, the intoxication process begins through the binding of the OP in the active site of the AChE enzyme inactivating it. Current treatments for people exposed to low doses of OP can be performed with atropine, oximes and benzodiazepines. Important remediation processes involve the employment of bioremediation techniques using different degrading enzymes, such as the Phosphotriesterase from Agrobacterium radiobacter and SMP-30. Due to the high number of intoxications annually, it is crucial to search for more potent and effective treatment methods, and in this line, the techniques involving bioremediation seem to be quite promising for this purpose.</p><p></p