3D-QSARpy: Combining variable selection strategies and machine learning techniques to build QSAR models

Quantitative Structure-Activity Relationship (QSAR) is a computer-aided technology in the field of medicinal chemistry that seeks to clarify the relationships between molecular structures and their biological activities. Such technologies allow for the acceleration of the development of new compounds by reducing the costs of drug design. This work presents 3D-QSARpy, a flexible, user-friendly and robust tool, freely available without registration, to support the generation of QSAR 3D models in an automated way. The user only needs to provide aligned molecular structures and the respective dependent variable. The current version was developed using Python with packages such as scikit-learn and includes various techniques of machine learning for regression. The diverse techniques employed by the tool is a differential compared to known methodologies, such as CoMFA and CoMSIA, because it expands the search space of possible solutions, and in this way increases the chances of obtaining relevant models. Additionally, approaches for select variables (dimension reduction) were implemented in the tool. To evaluate its potentials, experiments were carried out to compare results obtained from the proposed 3D-QSARpy tool with the results from already published works. The results demonstrated that 3D-QSARpy is extremely useful in the field due to its expressive results

Molecular approaches for structural characterization of a new potassium channel blocker from Tityus stigmurus venom: cDNA cloning, homology modeling, dynamic simulations and docking

AbstractPotassium channels are involved in the maintenance of resting membrane potential, control of cardiac and neuronal excitability, neurotransmitters release, muscle contractility and hormone secretion. The Tityus stigmurus scorpion is widely distributed in Northeastern Brazil and known to cause severe human envenomations, inducing pain, hypoesthesia, edema, erythema, paresthesia, headaches and vomiting. Most potassium channel blocking peptides that have been purified from scorpion venoms contain 30–40 amino acids with three or four disulfide bridges. These peptides belong to α-KTx subfamily. On the other hand, the β-KTx subfamily is poorly characterized, though it is very representative in some scorpion venoms. A transcriptomic approach of T. stigmurus scorpions developed by our group revealed the repertoire of possible molecules present in the venom, including many toxins of the β-KTx subfamily. One of the ESTs found, named TSTI0003C has a cDNA sequence of 538bp codifying a mature protein with 47 amino acid residues, corresponding to 5299Da. This β-KTx peptide is a new member of the BmTXKβ-related toxins, and was here named TstKMK. The three-dimensional structure of this potassium channel toxin of the T. stigmurus scorpion was obtained by computational modeling and refined by molecular dynamic simulations. Furthermore, we have made docking simulations using a Shaker kV-1.2 potassium channel from rats as receptor model and proposed which amino acid residues and interactions could be involved in its blockade

Aplicação do Método do Centro de Custos em uma Microempresa Individual: Estudo de Caso em uma Confeitaria

O presente estudo foi realizado em uma microempresa familiar no ramo de confeitaria, situada no sul de Santa Catarina, que tem como meta produzir artesanalmente e comercializar produtos de doçaria e confeitaria com tradição e qualidade buscando proporcionar satisfação aos clientes. O objetivo deste artigo é estudar os fatores de produção que influenciam nos custos de uma confeitaria, propondo a implantação do método do centro de custos na empresa, para isso será necessário identificar os itens de custos, dividir a empresa em centros de custos, realizar os rateios primário e secundário aos centros de custos; apropriar os custos aos produtos e calcular o preço de venda dos produtos e comparar com preços praticados. A metodologia é descritiva, de caráter quali-quantitativo e aplicação da técnica de pesquisa documental para coleta dos dados. Dessa forma, pretende-se possibilitar ao gestor um melhor conhecimento do processo produtivo, bem como estruturar a empresa em relação aos custos dos produtos, assim como seus preços unitários. Constatou-se que o estudo para a implantação do método do centro de custos gerou melhorias e maior segurança no esclarecimento dos custos em relação ao cenário anterior. Através dos resultados obtidos se pode verificar que os preços calculados dos produtos demonstraram-se muito distantes dos preços que estavam sendo praticados pela empresa

RENNER S.A: UMA ANÁLISE DOS OBJETIVOS DE DESENVOLVIMENTO SUSTENTÁVEL

A Responsabilidade Social Corporativa vem sendo atribuída ao pensamento de que a empresa não deve buscar somente por lucro. Atualmente com a grande competividade entre as empresas, a responsabilidade social deve ser vista com objetivo de crescimento, isso pelo fato de que o consumidor está comprando com consciência, pensando na sociedade, na economia e na sustentabilidade (JÚNIOR; BERTONCELLO, 2017). De acordo com a Brasil, Bolsa, Balcão (B3), o Índice de Sustentabilidade Empresarial (ISE) é uma análise comparativa feita em empresas listadas na B3, no aspecto sustentabilidade corporativa, visando dar conhecimento a empresa. A Organização das Nações Unidas (ONU) criou a Agenda 2030, definindo prioridades, metas para o desenvolvimento global até o ano 2030, composta por 17 Objetivos de Desenvolvimento Sustentável (ODS). O objetivo desse resumo é analisar os ODS presentes no relatório de sustentabilidade da Renner S.A, empresa integrante do ISE no período de 2017 a 2019. A pesquisa é descritiva, com análise documental e qualitativa/quantitativa. A empresa em estudo atua no segmento de comércio varejista e publica seu relatório de sustentabilidade desde o ano de 2013. Os resultados apontam que a empresa Renner vem se preocupando cada vez mais em se tornar sustentável. Nos relatórios de sustentabilidade, nos anos de 2017 e 2018 a ação da empresa que teve maior destaque em relação aos ODS foi: Energia Limpa e Acessível (ODS 7) visando a geração de energia solar, eólica e biomassa, com menor impacto global e a troca de lâmpadas fluorescentes para LED, dessa forma reduziu o custo de energia das lojas. No ano de 2019 a empresa focou em ações que envolveram Igualdade de gênero (ODS 5), Consumo de produção responsável (ODS 12) e Combate as alterações climáticas (ODS 13). Nesse contexto, as ações mais relevantes foram: a) empoderamento da mulher na cadeia têxtil; b) agir junto aos fornecedores para monitorar, controlar e fomentar processos produtivos responsáveis; c) promover a conscientização dos clientes para um consumo sustentável; e, d) assegurar estratégia de redução de emissões e mitigação das mudanças climáticas. Conclui-se que nos anos analisados, a Renner vem se preocupando em seguir as melhores práticas globais de transparência e gestão da sustentabilidade

Structural characterization of a novel peptide with antimicrobial activity from the venom gland of the scorpion Tityus stigmurus: Stigmurin

AbstractA new antimicrobial peptide, herein named Stigmurin, was selected based on a transcriptomic analysis of the Brazilian yellow scorpion Tityus stigmurus venom gland, an underexplored source for toxic peptides with possible biotechnological applications. Stigmurin was investigated in silico, by circular dichroism (CD) spectroscopy, and in vitro. The CD spectra suggested that this peptide interacts with membranes, changing its conformation in the presence of an amphipathic environment, with predominance of random coil and beta-sheet structures. Stigmurin exhibited antibacterial and antifungal activity, with minimal inhibitory concentrations ranging from 8.7 to 69.5μM. It was also showed that Stigmurin is toxic against SiHa and Vero E6 cell lines. The results suggest that Stigmurin can be considered a potential anti-infective drug

A plumieridine-rich fraction from Allamanda polyantha inhibits chitinolytic activity and exhibits antifungal properties against Cryptococcus neoformans

Cryptococcosis is a fungal infection caused mainly by the pathogenic yeasts Cryptococcus neoformans and Cryptococcus gattii. The infection initiates with the inhalation of propagules that are then deposited in the lungs. If not properly treated, cryptococci cells can disseminate and reach the central nervous system. The current recommended treatment for cryptococcosis employs a three-stage regimen, with the administration of amphotericin B, flucytosine and fluconazole. Although effective, these drugs are often unavailable worldwide, can lead to resistance development, and may display toxic effects on the patients. Thus, new drugs for cryptococcosis treatment are needed. Recently, an iridoid named plumieridine was found in Allamanda polyantha seed extract; it exhibited antifungal activity against C. neoformans with a MIC of 250 µg/mL. To address the mode of action of plumieridine, several in silico and in vitro experiments were performed. Through a ligand-based a virtual screening approach, chitinases were identified as potential targets. Confirmatory in vitro assays showed that C. neoformans cell-free supernatant incubated with plumieridine displayed reduced chitinase activity, while chitinolytic activity was not inhibited in the insoluble cell fraction. Additionally, confocal microscopy revealed changes in the distribution of chitooligomers in the cryptococcal cell wall, from a polarized to a diffuse cell pattern state. Remarkably, further assays have shown that plumieridine can also inhibit the chitinolytic activity from the supernatant and cell-free extracts of bacteria, insect and mouse-derived macrophage cells (J774.A1). Together, our results suggest that plumieridine can be a broad-spectrum chitinase inhibitor

The evaluation of in vitro antichagasic and anti-SARS-CoV-2 potential of inclusion complexes of β- and methyl-β-cyclodextrin with naphthoquinone

Funding Information: The authors thank the Coordination for the Improvement of Higher Education Personnel (CAPES) and the National Council for Scientific and Technological Development (CNPq) for their financial support. This study was supported by the CAPES — number 88887.505029/2020–00 . Cecilia Gomes Barbosa receives a scholarship funded by CAPES — number 88887.643352/2021–00 . Publisher Copyright: © 2023 Elsevier B.V.The compound 3a,10b-dihydro-1H-cyclopenta[b]naphtho[2,3-d]furan-5,10-dione (IVS320) is a naphthoquinone with antifungal and antichagasic potential, which however has low aqueous solubility. To increase bioavailability, inclusion complexes with β-cyclodextrin (βCD) and methyl-β-cyclodextrin (MβCD) were prepared by physical mixture (PM), kneading (KN) and rotary evaporation (RE), and their in vitro anti-SARS-CoV-2 and antichagasic potential was assessed. The formation of inclusion complexes led to a change in the physicochemical characteristics compared to IVS320 alone as well as a decrease in crystallinity degree that reached 74.44% for the IVS320-MβCD one prepared by RE. The IVS320 and IVS320-MβCD/RE system exhibited anti-SARS-CoV-2 activity, showing half maximal effective concentrations (EC50) of 0.47 and 1.22 μg/mL, respectively. Molecular docking simulation suggested IVS320 ability to interact with the SARS-CoV-2 viral protein. Finally, the highest antichagasic activity, expressed as percentage of Tripanosoma cruzi growth inhibition, was observed with IVS320-βCD/KN (70%) and IVS320-MβCD/PM (72%), while IVS320 alone exhibited only approximately 48% inhibition at the highest concentration (100 μg/mL).publishersversionpublishe

Structural assessment, toxicity, and increased antimicrobial activity

Scorpion venom is a rich source of biologically active components and various peptides with high-potential therapeutic use that have been characterized for their antimicrobial and antiproliferative activities. Stigmurin is a peptide identified from the Tityus stigmurus venom gland with high antibacterial and antiproliferative activities and low toxicity. Amino acid substitutions in peptides without a disulfide bridge sequence have been made with the aim of reducing their toxicity and increasing their biological activities. The purpose of this study was to evaluate the structural conformation and structural stability, as well as antimicrobial, antiproliferative, and hemolytic activities of two peptide analogs to Stigmurin, denominated StigA6 and StigA16. In silico analysis revealed the α-helix structure for both analog peptides, which was confirmed by circular dichroism. Data showed that the net charge and hydrophobic moment of the analog peptides were higher than those for Stigmurin, which can explain the increase in antimicrobial activity presented by them. Both analog peptides exhibited activity on cancerous cells similar to the native peptide; however, they were less toxic when tested on the normal cell line. These results reveal a potential biotechnological application of the analog peptides StigA6 and StigA16 as prototypes to new therapeutic agents.publishersversionpublishe

Tool for receptor dependent 4D-QSAR applied to set of T. cruzi trypanothione reductase inhibitors

Orientador: Márcia Miguel Castro FerreiraTese (doutorado) - Universidade Estadual de Campinas, Instituto de QuímicaResumo: LQTA-QSAR é uma metodologia computacional para QSAR-4D desenvolvida pelo Laboratório de Quimiometria Teórica e Aplicada implementada em um software de acesso livre. O método permite considerar simultaneamente as vantagens da representação molecular multiconformacional e os descritores de campos de interação. Esta tese apresenta a evolução da proposta inicial da metodologia LQTA-QSAR independente de receptores para uma abordagem dependente de receptores. Sua aplicação é demonstrada na construção de modelos de QSAR-4D para a previsão da atividade inibitória de compostos fenotiazínicos da enzima tripanotiona redutase. Foi obtido um modelo com bom poder de previsão (Qprev = 0,78) e com descritores de fácil interpretação. Tal modelo pode ser usado para a proposição de compostos que poderão vir a ser usados para o tratamento da doença de chagas. Para a filtragem e seleção de descritores foi necessário o desenvolvimento de um protocolo completamente distinto daquele disponível na literatura. Foi proposto um procedimento automatizado para identificar e eliminar descritores irrelevantes quando a correlação e um algoritmo que elimina descritores com distribuição díspar em relação à atividade biológica. Foram introduzidos também testes de validação de modelos QSAR nunca antes usados para modelos que utilizam descritores de campo de interação. O protocolo completo foi testado em três conjuntos de dados e os modelos obtidos tiveram capacidade de previsão superior aos da literatura. Os modelos mostraram ser bastante simples e robustos quando submetidos aos testes leave-N-out e y-randomizationAbstract: The New Receptor-Dependent LQTA-QSAR approach is proposed as a new 4D-QSAR method. The RD-LQTA-QSAR is an evolution to the receptor independent LQTA-QSAR. This approach make use of the simulation package GROMACS to carry out molecular dynamics simulations and generate a conformational ensemble profile for each compound. Such ensemble is used to build molecular interaction field based QSAR models, as in CoMFA. To verify the usefulness of the methodology it was chosen some phenothiazine derivatives that are specific competitive T. cruzi trypanothione reductase inhibitors. Using a combination of molecular docking and molecular dynamics simulations the binding mode of 38 phenotiazine derivatives was evaluated in a simulated induced fit approach. The ligands¿ alignment, necessary to the methodology, was performed using both ligand and binding site atoms hereafter enabling unbiased alignment. The obtained models were extensively validated by Leave-N-out cross-validation and y-randomization techniques to test robustness and absence of chance correlation. The final model presented Q LOO of 0.87 and R of 0.92 and suitable external prediction = 0.78. It is possible to use the obtained adapted binding site of to perform virtual screening and ligand structures based design, as well as using models descriptors to design new inhibitors. In the process of QSAR modeling, the relevance of correlation and distribution profiles were tested in order to improve prediction power. A set of tools to filter descriptors prior to variable selection and a protocol for molecular interaction field descriptors selection and models validation are proposed. The algorithms and protocols presents are quite simple to apply and enable a different and powerful way to build LQTA-QSAR modelsDoutoradoFísico-QuímicaDoutor em Ciência