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The octanol-water partition coefficient of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) was investigated using atomistic molecular dynamics simulations via thermodynamic integration and multistate Bennett acceptance ratio methods. The GAFF and CHARMM36 force fields were used with six water models widely used in molecular dynamics simulations. The OPC4 water model provided the best agreement with the experimental octanol-water partition coefficient of DPPC using the two force fields. However, there is still plenty of room for improvement in water models with correct estimation of surface tension that uses better and suitable non-bonded interaction parameters between water-water and water-DPPC. The Gibbs free energy of transferring DPPC from octanol to water phase was calculated to be 19.8 ± 0.3 and 20.2 ± 0.3 kcal mol-1, giving a partition coefficient of 14.5 ± 0.4 and 14.8 ± 0.3 for the GAFF and CHARMM36 force fields, respectively. This study reinforces the importance of developing new water models that reproduce experimental surface tensions to reconcile the water-water and water-DPPC non-bonded interactions and the existing discrepancy between experimental measurements of amphiphilic molecules that are important in many areas of scientific applications and industry such as biophysics, surfactant, colloids, membranes, medicine, nanotechnology, and food and pharmaceutical industries, and so on. It raises two important open questions: Is the experimental octanol-water partition coefficient of DPPC reliable? Or is its calculation accurate using the OPC4 water model? With respect to the experimental measurements, there may be non-treated aspects such as the formation of aggregates in aqueous phase and limit of detection of the applied method. And, in the calculation, some effects are not possible to be considered in a correct way or viable time such as calculating quantum effects, sampling all conformations, considering phase transitions, and correctly evaluating the intermolecular forces to estimate an accurate surface tension.Communicated by Ramaswamy H. Sarma.

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The interactions of the antiviral pentapeptide ATN-161 with the closed and open conformations of the α5ß1 integrin, the SARS-CoV-2 major protease, and the omicron variant spike protein complexed with hACE2 were studied using molecular docking and molecular dynamics simulation. Molecular docking was performed to obtain ATN-161 binding poses with these studied protein targets. Subsequently, molecular dynamics simulations were performed to verify the ligand stability at the binding site of each protein target. Pulling simulations, umbrella sampling, and weighted histogram analysis method were used to obtain the potential of mean force of each system and calculate the Gibbs free energy of binding for the ATN-161 peptide in each binding site of these protein targets. The results showed that ATN-161 binds to α5ß1 integrin in its active and inactive form, binds weakly to the omicron variant spike protein complexed with hACE2, and strongly binds to the main protease target.Communicated by Ramaswamy H. Sarma.

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The peptide Mucroporin and its analog Mucroporin-M1 were studied using the molecular docking and molecular dynamics simulation of their complexation with two protein targets, the Heptad Repeat 1 (HR1) domain and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2. The molecular docking of the peptide-protein complexes was performed using the glowworm swarm optimization algorithm. The lowest energy poses were submitted to molecular dynamics simulation. Then, the binding free energies of Mucroporin and its analog Mucroporin-M1 with these two protein targets were calculated using the Multistate Bennett Acceptance Ratio (MBAR) method. It was verified that the peptides/HR1 domain complex showed stability in the interaction site determined by molecular docking. It was also found that Mucroporin-M1 has a much higher affinity than Mucroporin to the HR1 protein target. The peptides showed similar stability and affinity at the NTP binding site in the RdRp protein. Additional experimental studies are needed to confirm the antiviral activity of Mucroporin-M1 and a possible mechanism of action against SARS-CoV-2. However, here we indicate that Mucroporin-M1 may have potential antiviral activity against the HR1 domain with the possibility for further peptide optimization.Communicated by Ramaswamy H. Sarma.

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OBJECTIVE: To analyze the perspective of Nurses Coordinators of Family Health Teams on the management of care for people with chronic illness in rural areas. METHOD: Qualitative approach exploratory study, carried out in a Health Region of Rio Grande do Sul, together with the Nurses in charge of the Units, between 2014 and 2015. The sample included seven participants. Data analysis was driven by thematic categorization and using NVIVO software. RESULTS: The thematic categories identified were: The administrative political organization of health care; The pluralities of rural impose specifics on care management and Strategies for management of care in the rural areas. FINAL CONSIDERATIONS: We pointed out elements of care management that are related not only to individual care, but also elements related to broader dimensions of health care, such as the social and political relationships that tension over the territories and that have implications to clinical practice.

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ABSTRACT Objective To analyze the perspective of Nurses Coordinators of Family Health Teams on the management of care for people with chronic illness in rural areas. Method Qualitative approach exploratory study, carried out in a Health Region of Rio Grande do Sul, together with the Nurses in charge of the Units, between 2014 and 2015. The sample included seven participants. Data analysis was driven by thematic categorization and using NVIVO software. Results The thematic categories identified were: The administrative political organization of health care; The pluralities of rural impose specifics on care management and Strategies for management of care in the rural areas. Final considerations We pointed out elements of care management that are related not only to individual care, but also elements related to broader dimensions of health care, such as the social and political relationships that tension over the territories and that have implications to clinical practice.

RESUMEN Objetivo Analizar la perspectiva de las Enfermeras Coordinadoras de los Equipos de Salud de la Familia sobre la gestión de la atención a las personas con enfermedades crónicas en el rural. Método Estudio exploratorio de abordaje cualitativo, realizado en una Región de Salud de Rio Grande do Sul junto a las Enfermeras en cargo de Coordinación de las Unidades de Salud de la Familia, entre 2014 y 2015, la muestra consistió en siete participantes. El análisis de datos se realizó mediante análisis de contenido temático, con soporte del software NVIVO. Resultados Categorías temáticas identificadas: La organización política administrativa de la atención en salud; Las pluralidades del rural imponiendo especificidades a la gestión del cuidado y Estrategias para la gestión del cuidado en el campo. Consideraciones finales Se apuntan elementos de la gestión del cuidado que están relacionados no sólo a la atención individual, sino también elementos vinculados a dimensiones más amplias de la atención en salud.

RESUMO Objetivo Analisar a perspectiva de Enfermeiras Coordenadoras de Equipes de Saúde da Família sobre a gestão do cuidado às pessoas em adoecimento crônico no rural. Método Estudo exploratório de abordagem qualitativa, realizado em uma Região de Saúde do Rio Grande do Sul, junto às Enfermeiras em cargo de Coordenação das Unidades de Saúde da Família, entre 2014 e 2015. A amostra foi constituída por sete participantes. A análise dos dados se deu por análise de conteúdo do tipo temática, com apoio do software NVIVO. Resultados Categorias temáticas identificadas: A organização político-administrativa da atenção em saúde; As pluralidades do Rural impondo Especificidades à Gestão do Cuidado e Estratégias para a gestão do cuidado no rural. Considerações finais Apontam-se elementos da gestão do cuidado que estão relacionados não só ao atendimento individual, mas também elementos ligados a dimensões mais amplas da atenção em saúde, como as relações sociais e políticas que tensionam os territórios e que têm implicações à prática clínica.

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BACKGROUND: ALDH-2 has been considered an important molecular target for the treatment of drug addiction due to its involvement in the metabolism of the neurotransmitter dopamine: however, the molecular basis for the selective inhibition of ALDH-2 versus ALDH-1 should be better investigated to enable a more pragmatic approach to the design of novel ALDH-2 selective inhibitors. OBJECTIVE: In the present study, we investigated the molecular basis for the selective inhibition of ALDH-2 by the antioxidant isoflavonoid daidzin (IC50 = 0.15 µM) compared to isoform 1 of ALDH through molecular dynamics studies and semiempirical calculations of the enthalpy of interaction. METHODS: The applied methodology consisted of performing the molecular docking of daidzin in the structures of ALDH-1 and ALDH-2 and submitting the lower energy complexes obtained to semiempirical calculations and dynamic molecular simulations. RESULTS: Daidzin in complex with ALDH-2 presented directed and more specific interactions, resulting in stronger bonds in energetic terms and, therefore, in enthalpic gain. Moreover, the hydrophobic subunits of daidzin, in a conformationally more restricted environment (such as the catalytic site of ALDH-2), promote the better organization of the water molecules when immersed in the solvent, also resulting in an entropic gain. CONCLUSION: The molecular basis of selective inhibition of ALDH-2 by isoflavonoids and related compounds could be related to a more favorable equilibrium relationship between enthalpic and entropic features. The results described herein expand the available knowledge regarding the physiopathological and therapeutic mechanisms associated with drug addiction.

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The deleterious effects of nerve agents over the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) turned these compounds into the most dangerous chemical weapons known. Among the antidotes in use today against these agents, oximes in combination with other drugs are the only treatment with any action. HI-6 and 2-PAM are cationic oximes proved to be effective for the reactivation of AChE inhibited by the nerve agents VX and sarin (GB). However, when it comes to reactivation of AChE inside the central or peripheral nervous systems, charged molecules present low diffusion due to low penetration through the blood-brain barrier. Uncharged oximes appear as an interesting alternative to solve this problem, but the development and enhancement of more efficient uncharged oximes capable of reactivating human AChE is still necessary. Given the limitations for in vivo and in vitro experimental studies with nerve agents, modeling is an important tool that can contribute to a better understanding of factors that may affect the efficiency of uncharged oximes. In order to investigate the interaction and behavior of cationic and uncharged oximes, we performed here molecular docking, molecular dynamics simulations, and binding energies calculations of the known cationic oximes HI-6 and 2-PAM plus four uncharged oximes found in the literature, complexed with human AChE (HssACHE) conjugated with the nerve agents VX and GB. The uncharged oximes showed different behaviors, especially RS194B, which presented stability inside AChE-VX, but presented free binding energy lower than cationic oximes, suggesting that structural alterations could favor its interactions with these complexes. In contrast, HI-6 and 2-PAM showed higher affinities with more negative binding energy values and larger contribution of the amino acid Asp74, demonstrating the importance of the quaternary nitrogen to the affinity and interaction of oximes with AChE-GB and AChE-VX conjugates.

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Coxiella burnetii is a gram-negative bacterium able to infect several eukaryotic cells, mainly monocytes and macrophages. It is found widely in nature with ticks, birds, and mammals as major hosts. C. burnetii is also the biological warfare agent that causes Q fever, a disease that has no vaccine or proven chemotherapy available. Considering the current geopolitical context, this fact reinforces the need for discovering new treatments and molecular targets for drug design against C. burnetii. Among the main molecular targets against bacterial diseases reported, the enzyme dihydrofolate reductase (DHFR) has been investigated for several infectious diseases. In the present work, we applied molecular modeling techniques to evaluate the interactions of known DHFR inhibitors in the active sites of human and C. burnetii DHFR (HssDHFR and CbDHFR) in order to investigate their potential as selective inhibitors of CbDHFR. Results showed that most of the ligands studied compete for the binding site of the substrate more effectively than the reference drug trimethoprim. Also the most promising compounds were proposed as leads for the drug design of potential CbDHFR inhibitors.

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In the present work, we propose to design drugs that target the enzyme dihydrofolate redutase (DHFR) as a means of a novel drug therapy against plague. Potential inhibitors of DHFR from Yersinia pestis (YpDHFR) were selected by virtual screening and subjected to docking, molecular dynamics (MD) simulations, and Poisson-Boltzmann surface area method, in order to evaluate their interactions in the active sites of YpDHFR and human DHFR (HssDHFR). The results suggested selectivity for three compounds that were further used to propose the structures of six new potential selective inhibitors for YpDHFR.

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