RESUMO
Ricin is a potent cytotoxin with no available antidote. Its catalytic subunit, RTA, damages the ribosomal RNA (rRNA) of eukaryotic cells, preventing protein synthesis and eventually leading to cell death. The combination between easiness of obtention and high toxicity turns ricin into a potential weapon for terrorist attacks, urging the need of discovering effective antidotes. On this context, we used computational techniques, in order to identify potential ricin inhibitors among approved drugs. Two libraries were screened by two different docking algorithms, followed by molecular dynamics simulations and MM-PBSA calculations in order to corroborate the docking results. Three drugs were identified as potential ricin inhibitors: deferoxamine, leucovorin and plazomicin. Our calculations showed that these compounds were able to, simultaneously, form hydrogen bonds with residues of the catalytic site and the secondary binding site of RTA, qualifying as potential antidotes against intoxication by ricin.Communicated by Ramaswamy H. Sarma.
Assuntos
Ricina , Antídotos , Reposicionamento de Medicamentos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ricina/química , Ricina/metabolismo , Ricina/farmacologiaRESUMO
Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.
Assuntos
Ricina/antagonistas & inibidores , Ricina/química , Algoritmos , Sítios de Ligação , Substâncias para a Guerra Química/química , Descoberta de Drogas , Ligação de Hidrogênio , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura MolecularRESUMO
Objective: To assess potential for early detection of oral infection by B. anthracis spores for preparedness of a bioterrorism attack. Material and Methods: The laboratory study used saliva with a range of initial anthrax concentrations, to compare detection by direct observation from conventional blood agar culture and by anthrax-specific PCR after a shorter culture in BHI broth. Three types of saliva were collected: stimulated saliva, unstimulated/whole saliva, and unstimulated/whole saliva with antibiotic treatment (for negative control). Using bivariate Kruskal-Wallis and Mann-Whitney tests for statistical analysis for factors that could affecting anthrax detection, significant differences between the test groups was assumed at p<0.05. Results: From unstimulated whole saliva heat shock treated at 62.50C, B. anthracis growth was detected with both methods. PCR detection from a BHI broth culture could shorten the time to diagnosis in comparison to conventional culture in blood agar. Conclusion: Saliva can provide useful samples for diagnosis of oropharyngeal anthrax. In comparison to conventional culture on blood agar, shorter-term culture in BHI broth provides potential for earlier detection and diagnosis.
Assuntos
Saliva/microbiologia , Bioterrorismo , Diagnóstico Precoce , Antraz/microbiologia , Estatísticas não Paramétricas , IndonésiaRESUMO
Aflatoxins are secondary metabolites of the fungi Aspergillus flavus and A. parasiticus. Among them, aflatoxin B1 (AFB1) is the most frequent type in nature and the most carcinogenic for mammals. It can contaminate many kinds of food like seeds, oil, olives, milk, dairy products, corn and meat, causing acute and chronic damages to the organism, especially in the liver, being, for this reason, considered highly hepatotoxic. AFB1 is also a mixed inhibitor of the enzyme acetylcholinesterase (AChE). This fact, together with its high toxicity and carcinogenicity, turns AFB1 into a potential chemical and biological warfare agent, as well as its metabolites. In order to investigate this, we performed inedited molecular modeling studies on the interactions of AFB1 and its metabolites inside the peripheral anionic site of human AChE (HssAChE), to verify their stability, suggest the preferential ways of inhibition, and compare their behavior to each other. Our results suggest that all metabolites can be better inhibitors of HssAChE than AFB1 and that AFBO and AFM1, the most toxic and carcinogenic metabolites of AFB1, are also the most effective HssAChE inhibitors among the AFB1 metabolites. Communicated by Ramaswamy H. Sarma.
Assuntos
Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Aflatoxina B1/química , Aflatoxina B1/metabolismo , Metaboloma , Modelos Moleculares , Ânions , Humanos , Ligação de Hidrogênio , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , TermodinâmicaRESUMO
RESUMEN Fundamento: el control de enfermedades transmisibles contribuye al empleo ilegítimo de los agentes biológicos, de manera inicial con fines bélicos o criminales y en la actualidad con fines terroristas. Objetivo: describir la problemática del empleo de las armas biológicas, sus diferentes aristas y en su forma actual con fines terroristas y los aspectos que prohíben su uso según la normativa internacional vigente. Métodos: se realizó una revisión bibliográfica con el método de análisis bibliográfico con una búsqueda realizada entre los años 2000 al 2017, donde se consultaron bases de datos especializadas y se seleccionaron 31 publicaciones científicas sobre el tema. Desarrollo: se realizó un análisis del tema de la guerra biológica basado en los agentes utilizados y la amenaza que constituye su empleo, pues provocan enfermedades y causan la muerte al afectar la salud de los seres vivos y el medio ambiente. Son dañinas e incluyen conocimientos de ciencia, tecnología, ingeniería e involucran otras áreas, como la economía, el derecho, el marco jurídico que limita o no la obtención de materiales y los aspectos psicológicos ante tales ataques. Los avances tecnológicos en Biología e Ingeniería genética de las últimas décadas posibilitan modificar y crear nuevos microorganismos más resistentes al tratamiento y en particular en la búsqueda de inoculación de enfermedades como el cáncer. La biodefensa es el conjunto de medidas para la prevención y actuación frente a una alerta sanitaria donde está implicado el uso de los agentes biológicos con fines bélicos. Conclusiones: los agentes biológicos se utilizan como armas para ocasionar daños en circunstancias de guerra biológica y bioterrorismo, por ser de forma potencial el arma más destructiva conocida por la humanidad que implica aspectos políticos, económicos, científico-tecnológicos, jurídicos y psicológicos, por lo que la biodefensa protege a las personas y el medio ambiente con el uso de medidas sanitarias contra dichos agentes.
ABSTRACT Background: the control of transmittable diseases contributes to the illegitimate use of biological agents, initially for war or criminal purposes and currently for terrorist purposes. Objective: to describe the problem of the use of biological weapons, its different edges and in its current form for terrorist purposes and the aspects that prohibit its use according to current international regulations. Methods: a bibliographic review was made with the bibliographic analysis method with a search conducted between 2000 and 2017, where specialized databases were consulted and 31 scientific publications on the subject were selected. Development: an analysis on the issue of biological warfare was made based on the agents used and the threat that constitutes their use, since they cause diseases and cause death by affecting the health of living beings and the environment. They are harmful and include knowledge of science, technology, engineering and involve other areas, such as economics, law, the legal framework that limits or not the obtaining of materials and the psychological aspects of such attacks. The technological advances in Biology and Genetic engineering of recent decades make it possible to modify and create new microorganisms that are more resistant to treatment and in particular in the search for the inoculation of diseases such as cancer. The biodefense is the set of measures for the prevention and action facing a sanitary alert where the use of the biological agents with war aims is implied. Conclusions: biological agents are used as weapons to cause damage in circumstances of biological warfare and bioterrorism, as it is potentially the most destructive weapon known to humanity that involves political, economic, scientific-technological, legal and psychological aspects, which is why biodefense protects people and the environment with the use of sanitary measures against above-mentioned agents.
RESUMO
In the present work, we applied docking and molecular dynamics techniques to study 11 compounds inside the enzymes dihydrofolate reductase (DHFR) from the biological warfare agent Bacillus anthracis (BaDHFR) and Homo sapiens sapiens (HssDHFR). Six of these compounds were selected for a study with the mutant BaF96IDHFR. Our results corroborated with experimental data and allowed the proposition of a new molecule with potential activity and better selectivity for BaDHFR.
Assuntos
Antibacterianos/química , Bacillus anthracis/química , Proteínas de Bactérias/química , Antagonistas do Ácido Fólico/química , Bibliotecas de Moléculas Pequenas/química , Tetra-Hidrofolato Desidrogenase/química , Bacillus anthracis/enzimologia , Bacillus anthracis/genética , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/genética , Armas Biológicas , Domínio Catalítico , Desenho de Fármacos , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Mutação , Especificidade da Espécie , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/genética , TermodinâmicaRESUMO
Fundamento: la preparación del profesional de la salud para enfrentar las consecuencias de las armas químicas y biológicas en humanos, es una misión de la universidad médica cubana. Objetivo: evaluar la factibilidad y pertinencia de una estrategia pedagógica de superación profesional médica para la enseñanza del diagnóstico y tratamiento de las consecuencias del empleo de las armas químicas y biológicas en humanos. Métodos: se realizó una investigación que culminó con la aplicación de un pre-experimento pedagógico en la sede universitaria Hospital Militar de Holguín, durante el curso 2010-2011. La muestra estuvo constituida por 20 especialistas en Medicina General Integral. Se utilizaron métodos teóricos: histórico-lógico, analítico-sintético y sistémico estructural y funcional; empíricos: la encuesta, criterio de especialistas por el método Delphi; del matemático: la estadística descriptiva con distribución de frecuencias absoluta y en porcientos y la prueba de signos. Resultados: se identificaron insuficiencias en los médicos para el diagnóstico y tratamiento de las consecuencias de las armas químicas y biológicas en humanos, por lo cual se diseñó y aplicó una estrategia pedagógica para la apropiación de los conocimientos y habilidades necesarios en estos casos. Conclusiones: la estrategia elaborada permitió resolver las dificultades para el desarrollo del proceso enseñanza aprendizaje de las enfermedades que resultan del empleo de las armas químicas y biológicas, y una mejor preparación en los médicos en cuanto al diagnóstico y tratamiento de ellas. Los especialistas consideran la estrategia de muy adecuada y bastante adecuada, lo que demuestra el grado de pertinencia y relevancia para su aplicación.
Background: the professional training in order to face the consequences in human beings of the chemical and biological weapons is a mission of the Cuban medical university. Objective: to devise a strategy for the teaching of the diagnosis and treatment of the effects in human beings of the chemical and biological weapons. Methods: a research project was done that culminated in the application of a pedagogical pre-experiment at the University Venue Military Hospital of Holguín during the 2010-2011 academic year. The sample was chosen through a non-probabilistic sampling, composed of 20 specialists in Integral General Medicine. Theoretical methods were used: historical-logical, analytical-synthetic, inductive-deductive, modeling and systemic, structural and functional; empirical: Delphi method and survey; mathematical: descriptive statistics with distribution of absolute frequency and in percentage. Results: insufficiencies were identified among the doctors for the diagnosis and treatment of the effects in human beings of chemical and biological weapons, being this reason why a pedagogical strategy was designed and applied for the acquisition of the knowledge and skills that are necessary in these cases. Conclusions: the designed strategy allows to solve the difficulties for the development of the learning-teaching process of the illnesses resulting from the use of chemical and biological weapons, as well as a better training in doctors regarding their diagnosis and treatment. The specialists assessed the strategy in general as very adequate, what shows the degree of relevance and pertinence for its application.
Assuntos
Competência Profissional , Substâncias para a Guerra Química , Armas Biológicas , Clínicos Gerais/educaçãoRESUMO
Os fundamentalismos surgiram no Ocidente a partir de questões religiosas e posteriormente difundiram-se para outras partes do mundo tomando outras conotações, principalmente políticas. As técnicas de manipulação genética difundiram-se pelas universidades, que formam mestres e doutores com os conhecimentos básicos sobre clonagem gênica, que se tornou de domínio público. Todos os insumos para clonagem gênica podem ser adquiridos por meio de catálogos via internet. Podem-se recrutar profissionais fanáticos e com a competência para a manipulação genética de organismos patogênicos, lado perverso da biotecnologia. Os conflitos étnicos, culturais e religiosos estão associados a um cenário de contrastes entre os países ricos e carentes de matéria-prima e aqueles pobres, mas detentores de insumos básicos e energia, e atingem a sua forma mais aguda nos fundamentalismos. Grupos de fanáticos têm pleno acesso a essa biotecnologia. Estariam assim as populações civis vulneráveis aos ataques do bioterrorismo com armas biológicas geneticamente modificadas?.
Fundamentalism arose in the West based in religious matters and afterward diffused to other parts of theworld with other connotations, especially political. Genetic manipulation techniques spread to universities,which has given masters and doctors the basic knowledge on gene cloning, which has become public domain.All inputs for gene cloning may be obtained through online catalogs. Fanatic professionals may be recruited,with qualification for genetic manipulation of pathogenic organisms, the negative side of biotechnology. Eth-nic, cultural and religious conflicts are linked to a series of contrasts between countries that are rich but witha lack of raw materials and the poor countries that possess basic input and energy sources, when it reachesthe highest fundamentalist form. Fanatic groups have complete access to this biotechnology. Are civilian po-pulations in vulnerable to bioterrorist attacks involving genetically modified biological weapons?
Assuntos
Humanos , Masculino , Feminino , Guerra Biológica , Armas Biológicas , Biotecnologia , Bioterrorismo , Clonagem Molecular , DNA Recombinante , Engenharia Genética , GenéticaRESUMO
O bioterrorismo é hoje uma ameaça real em todo o mundo. Considerando-se que as ações de bioterrorismo utilizam agentes biológicos capazes de promover grandes epidemias e sobrecarga nos sistemas de saúde de qualquer cidade, estado ou país, o bioterrorismo passa a ser não apenas uma preocupação de governantes e militares, mas também dos profissionais da área da saúde. Este artigo discute, através de uma revisão bibliográfica, nas bases de dados LILACS, MEDLINE, SciELO e REPIDISCA, no período de 1997 a 2007, as características das publicações nacionais relacionadas ao bioterrorismo, o tipo de agentes biológicos estudados e o conhecimento já existente no país para fazer frente a um evento de bioterrorismo, a fim de subsidiar com informação os profissionais que irão atuar em ações de primeira resposta aos eventos de bioterrorismo e que são imprescindíveis para reduzir o número de vítimas.
Today, bioterrorism is a real threat in the whole world. Considering the actions of bioterrorism by using biological agents capable of promoting great epidemics and overload in the health systems of any city, state or country, the bioterrorism is not only a health professional concern, but government and military also. This article discusses a bibliographical review done in the LILACS, MEDLINE, SciELO and REPIDISCA databases, during the period of 1997 the 2007, the characteristics of related national publications to the bioterrorism, the type of biological agents studied, and the existing knowledge in the country to face a bioterrorism event, in order to feed with information the professionals who will act in first reply to the bioterrorism events and that are essential to reduce the number of victims.