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Estudos estruturais de duas 3 (Fenoximetil)-4-fenilbut-3-en-onas e docking no fator letal (LF) do bacillus anthracis (Antraz) / Structural studies of two 3(phenoxymethyl)-4-phenylbut-3-enones and docking in the lethal factor (LF) of bacillus anthracis (Antraz)Nucci Junior, Paulo Roberto 28 August 2014 (has links)
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Previous issue date: 2014-08-28 / In this work the crystal structures of two 3 (phenoxymethyl)-4-phenylbut-3-en-ones were determined and the resulting 3D strutures were used as input for docking studies in the lethal factor (LF) of bacillus anthracis. The results were then compared with those of a known inhibitor.(3E)-3-(4-nitrophenoxymethyl)-4- phenylbut-3-en-2-one (1): the conformation about the C═C double bond [1.348 (2) Å] is E with the ketone group almost co-planar [C C C C torsion angle = 7.2 (2)°] but the phenyl group twisted away [C C C C =160.93 (17)°]. The terminal aromatic rings are almost perpendicular to each other [dihedral angle = 81.61 (9)°] giving themolecule an overall U-shape. The crystal packing feature benzene-C H O (aldehyde) contacts that lead to supramolecular helical chains along the b axis. These are connected by π π interactions between benzene and phenyl rings [inter-centroid distance = 3.6648 (14) Å] resulting in the formation of a supramolecular layer in the bc plane.(3E)-3-(2,4-dinitrophenoxymethyl)-4-phenylbut- 3-en-2-one (2): the conformation about the C=C double bond [1.345 (2) Å] is E, with the ketonemoiety almost coplanar [C C C C torsion angle = 9.5(2) °] along with the phenyl ring [C C C C = 5.9 (2) °]. The aromatic rings are almost perpendicular to each other [dihedral angle = 86.66 (7) °]. The 4-nitro moiety is approximately coplanar with the benzene ring to which it is attached [O N C C = 4.2 (2) °], whereas the one in the ortho position is twisted [O N C C = 138.28 (13) °]. The molecules associate via C H O interactions, involving both O atoms from the 2-nitro group, to form a helical supramolecular chain along [010]. Nitro nitro N O interactions [2.8461 (19) Å] connect the chains into layers that stack along[001]. The docking results, using as a target the lethal factor (LF) of bacillus anthracis, show that both Compound 1 and 2 located themselves in the same cavity where the known inhibitor is located, and making most of the interactions this last one does with the amino acid residues that are important for the enzyme activity, so that it can be postulated that they can be also inhibitors. Moreover, Compound 1adopts a pose closer to that of the inhibitor whereas Compound 2 is rotated so that an important interaction is missed, this may indicate that this last one can be a less effective inhibitor than Compound 1. / Neste trabalho, as estruturas cristalinas dos dois 3(fenoximetil)-4-fenilbut-3-en-onas foram determinadas e as estruturas 3D resultantes foram utilizadas como entrada para estudos de docking no fator letal (LF) do bacillus anthracis. Os resultados foram comparados com os de um inibidor conhecido (3E)-3-(4-nitrofenoximetil)-4- fenilbut-3-en-2-ona(1): a conformação ao redor da ligação dupla C═C[1,348 (2) Â] é E, com o grupo cetona quase co-planar [ângulo de torção C-C-C-C =7,2(2) °], mas o grupo fenila está torcido [C-C-C-C =160,93(17)°]. Os anéis aromáticos terminais estão quase perpendiculares entre eles [ângulo diedro =81,61(9)°], o que dá a molécula a forma de U. O empacotamento cristalino apresenta contatos benzeno- C-H O (cetona) que levam a cadeias supramoleculares helicoidais ao longo do eixo b. Estas por sua vez estão ligadas através de interações π-π entre o benzeno e o anel fenila, [distância inter-centróide = 3,6648(14)Å], resultando na formação de uma camada supramolecular no plano bc (3E)-3-(2,4-dinitrofenoximetil)-4-fenilbut- 3-en-2-ona (2): a conformação em torno da ligação dupla C=C[1,345 (2) Å] é E, com a cetona quase coplanar [ângulo de torção C-C-C-C =9,5(2)°], juntamente com o anel de fenila [C-C-C-C =5,9(2)°]. Os anéis aromáticos estão quase perpendiculares entre si [ângulo diedro =86,66(7)°]. O grupo 4-nitro é aproximadamente coplanar ao anel benzeno ao qual está ligado [S-N-C-C =4,2(2) °], enquanto que o grupo na posição orto está torcido [S-N-C-C =138,28(13)°]. As moléculas se associam através de interações C-H...O, envolvendo ambos os átomos de O do grupo 2-nitro, de modo a formar uma cadeia supramolecular helicoidal ao longo da direção [010]. Interações nitro-nitro N...O [2,8461 (19)Å] unem as cadeias em camadas que se empilham ao longo da direção [001]. Os resultados do docking molecular, utilizando como alvo o fator letal (LF) de bacillus anthracis, mostram que tanto o Composto 1 como o 2, colocaram-se na mesma cavidade que o inibidor conhecido está localizado, e fazem a maior parte das interações que este último faz com os resíduos de aminoácidos, que são importantes para a atividade da enzima, de modo que também podem ser inibidores. Além disso, o Composto 1 adota uma pose mais próxima da do inibidor, ao passo que o Composto 2 está rodado de modo que uma interação importante é perdida, isso pode indicar, que este último, pode ser um inibidor menos eficaz do que o Composto 1.
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Διαμορφωτική μελέτη μέσω φασματοσκοπίας NMR του καταλυτικού τομέα του θανατηφόρου παράγοντα του άνθρακα και μελέτη των συμπλόκων του με πεπτιδικά υποστρώματα μέσω βιομοριακής προσομοίωσηςΔάλκας, Γεώργιος 25 January 2012 (has links)
Η θανατηφόρος δράση του βακτηρίου του άνθρακα (Bacillus anthracis), στο οποίο οφείλεται η καλούμενη ως νόσος του άνθρακα, εντοπίζεται στη συνεργό δράση τριών εκλυόμενων τοξινών του και ειδικότερα στην πρωτεολυτική δράση του θανατηφόρου παράγοντα (anthrax Lethal Factor, LF). Ο LF είναι μία μεταλλοπρωτεάση ψευδαργύρου και ισχυρή τοξίνη, η οποία απελευθερώνεται στον οργανισμό στα πρώτα στάδια προσβολής του ατόμου από το βακτήριο. Το ενεργό/καταλυτικό κέντρο του αναγνωρίζει και υδρολύει με εξαιρετική εξειδίκευση πεπτιδικά υποστρώματα ΜΚΚ κινασών, αναστέλλοντας τις διαδικασίες μεταγωγής σήματος στα κύτταρα του μολυσμένου ξενιστή επιφέροντας το θάνατό του. Από την άλλη, η εξειδικευμένη πρωτεολυτική ικανότητα του LF έναντι αυτών των κινασών, οι οποίες πρόσφατα συσχετίστηκαν με ανάπτυξη καρκινικών όγκων, ενδέχεται να αποτελέσει μια καινοτόμο θεραπευτική οδό για την αντιμετώπιση καρκινικών όγκων εν τη γενέση τους. Ωστόσο, ο μηχανισμός της αλληλεπίδρασης σε μοριακό επίπεδο και της πρωτεολυτικής διάσπασης των υποστρωμάτων του LF παραμένει μέχρι και σήμερα αδιευκρίνιστος και συνεπώς χρήζει ιδιαίτερης μελέτης.
Προς αυτή την κατεύθυνση εστιάστηκε το ενδιαφέρον της διατριβής έχοντας ως πρωτογενείς στόχους την in silico μελέτη της αλληλεπίδρασης, σε μοριακό επίπεδο, του καταλυτικού κέντρου του LF με τα υποστρώματα των ΜΚΚ κινασών που υδρολύει, και την μελέτη μέσω Φασματοσκοπίας NMR της δομής και δυναμικής του ενεργού κέντρου του LF σε ελεύθερη μορφή, το οποίο ευρίσκεται στο C-τελικό άκρο του.
Με την εφαρμογή τεχνικών προσομοίωσης πρόσδεσης και μοριακής δυναμικής πραγματοποιήθηκε in silico μελέτη των συμπλόκων LF-υποστρώματα, και προσδιορίστηκε ένα ευρύ φάσμα αλληλεπιδράσεων, όχι μόνο γύρω από το μεταλλικό/καταλυτικό κέντρο αλλά και σε απόσταση 20 Å στην περιοχή δέσμευσης του Zn2+, υποδεικνύοντας έτσι τους δομικούς παράγοντες που πιθανόν καθορίζουν το είδος της αλληλεπίδρασής ενζύμου με τις κινάσες που υδρολύει, παρέχοντας έτσι σημαντικές πληροφορίες για τον σχεδιασμό και την αναζήτηση βιοδραστικών μορίων με φαρμακευτικό ενδιαφέρον έναντι στον LF. Τα δεδομένα αυτά μπορούν επίσης να αξιοποιηθούν σε μελέτες δομής-δράσης με σημειακές και/ή πολλαπλές μεταλλάξεις.
Με την χρήση φασματοσκοπίας NMR, πραγματοποιήθηκε μελέτη της δομής και δυναμικής του ενεργού κέντρου του LF σε ελεύθερη μορφή (apoLF672-776). Η επίλυση των τρισδιάστατων NMR δομών του apoLF672-776 έδωσαν μια εξαιρετικά σαφή εικόνα για τη δομή του ενεργού κέντρου του LF, το οποίο βρίσκεται σε συμφωνία με τις υπάρχουσες κρυσταλλικές δομές. Τα συγκεκριμένα ΝΜR δεδομένα μπορούν να αξιοποιηθούν σε μελέτες με NMR υπό το καθεστώς αλληλεπίδρασης του LF με τα πεπτιδικά υποστρώματά του και χαρακτηρισμό της δυναμικής της αλληλεπίδρασης, όπως επίσης και τον υπολογισμό της συγγένειας δέσμευσής τους. / The anthrax toxin of the bacterium Bacillus anthracis consists of three distinct proteins, one of which is the anthrax lethal factor (LF). LF is a gluzincin Zn-dependent, highly specific metalloprotease with a molecular mass of ~90 kDa that cleaves most isoforms of the family of mitogen-activated protein kinase kinases (MEKs/MKKs) close to their amino termini, resulting in the inhibition of one or more signaling pathways. Previous studies on the crystal structures of uncomplexed LF and LF complexed with the substrate MEK2 or a MKK-based synthetic peptide provided structure-activity correlations and the basis for the rational design of efficient inhibitors. However, in the crystallographic structures, the substrate peptide was not properly oriented in the active site due to the absence of the catalytic zinc atom.
The primary target of the thesis was to examine in silico the LF-MEK/MKK interaction along the catalytic channel up to a distance of 20 Å from the zinc atom, using docking and molecular dynamics protocols. This residue-specific view of the enzyme-substrate interaction provides valuable information about: (i) the substrate selectivity of LF and its inactivation of MEKs/MKKs, (an issue highly important not only to anthrax infection, but also to the pathogenesis of cancer), and (ii) the discovery of new, previously unexploited, hot-spots of the LF catalytic channel that are important in the enzyme/substrate binding and interaction. Given the importance of the interaction between LF and substrate for the development of anti-anthrax agents as well as the potential treatment of nascent tumours, the analysis of the structure and dynamic properties of the LF catalytic site are essential to elucidate its enzymatic properties. The thesis interest was oriented then to the solution structure of the catalytic domain of apo LF and present data on its dynamics. The solution nuclear magnetic resonance (NMR) structure and mobility studies of the catalytic domain of apoLF672-776 reveals that the conformation of the C-terminal construct of the LF catalytic domain and the orientation of the six helical motifs are remarkably similar to the native structure, indicating the LF polypeptides catalytic site as reliable models of the enzyme active centre.
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Assessment Of Molecular Interactions Via Magnetic Relaxation: A Quest For Inhibitors Of The Anthrax ToxinSantiesteban, Oscar 01 January 2012 (has links)
Anthrax is severe disease caused by the gram-positive Bacillus anthracis that can affect humans with deadly consequences. The disease propagates via the release of bacterial spores that can be naturally found in animals or can be weaponized and intentionally released into the atmosphere in a terrorist attack. Once inhaled, the spores become activated and the anthrax bacterium starts to reproduce and damage healthy macrophages by the release of the anthrax toxin. The anthrax toxin is composed of three virulent factors: (i) anthrax protective antigen (APA), (ii) anthrax lethal factor (ALF), and (iii) anthrax edema factor (AEF) that work in harmony to effectuate the lethality associated with the disease. Out of the two internalized factors, ALF has been identified to play a critical role in cell death. Studies in animals have shown that mice infected with an anthrax strain lacking ALF survive the infection whereas when ALF is present the survivability of the mice is eliminated. Although the current therapy for anthrax is antibiotic treatment, modern medicine faces some critical limitations when combating infections. Antibiotics have proven very efficient in eliminating the bacterial infection but they lack the ability to destroy or inhibit the toxins released by the bacteria. This is a significant problem since ALF can remain active in the body for days after the infection is eliminated with no way of inhibiting its destructive effects. The use of inhibitors of ALF is an attractive method to treat the pathogenesis of anthrax infections. Over the last decade several inhibitors of the enzymatic activity of ALF have been identified. In order to identify inhibitors of ALF a variety of screening approaches such as library screenings, Mass Spectroscopy- based screenings and scaffold-based NMR screening have been used. Results from these iv screening have yielded mainly small molecules that can inhibit ALF in low micromolar to nanomolar concentrations. Yet, although valuable, these results have very little significance with regards to treating ALF in a real-life scenario since pharmaceutical companies are not willing to invest in further developing these inhibitors. Furthermore, the low incidence of inhalation anthrax, the lack of a market for an ALF inhibitor, and the expenses associated with the approval process of the FDA, have hindered the motivation of pharmaceutical companies to pursuit these kind of drugs. Therefore we have screened a small-molecule library of FDA approved drugs and common molecules in order to identify currently approved FDA drugs that can also inhibit ALF (Chapter III). The screening revealed that five molecules: sulindac, fusaric acid, naproxen, ketoprofen and ibuprofen bound to either ALF or APA with sulindac binding both. Additionally, we have developed a nanoparticle-based screening method that assesses molecular interactions by magnetic relaxation changes (Chapter II). Using this assay, we were able to accurately measure the dissociation constants of different interactions between several ligands and macromolecules. Moreover, we have used computational docking studies to predict the binding site of the identified molecules on the ALF or APA (Chapter IV). These studies predicted that two molecules sulindac and fusaric acid could be potential inhibitors of ALF since they bind at the enzymatic pocket. As a result, we tested the inhibitory potential of these molecules as well as that of the metabolic derivatives of sulindac (Chapter V). Results from these studies provided conclusive evidence that fusaric acid and sulindac were both strong inhibitors of ALF. Furthermore, the metabolic derivatives of sulindac, sulindac sulfide and sulindac sulfone v also inhibited ALF. Overall, taking together these results we have discovered the alternate use of a currently used drug for the treatment of ALF pathogenesis.
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Étude structurale conformationnelle des toxines de l’anthrax par cryo-microscopie et dynamique moléculaireFabre, Lucien 01 1900 (has links)
Les toxines de l’anthrax font partie de la famille des toxines A-B dans laquelle la moitié B se fixe à la membrane de la cellule permettant par la suite la translocation de la moitié A. Dans le cas de l’anthrax, la moitié B est représentée par le Protective Antigen (PA) et la moitié A par les deux protéines Edema Factor (EF) et Lethal Factor (LF). Après le recrutement par les récepteurs cellulaires (CMG2 et TEM8), PA s’organise en heptamère. Il peut fixer jusqu'à 3 ligands (EF et LF) avant d'être endocyté. Les modèles actuels de PA suggèrent que la baisse de pH à l’intérieur des endosomes permet un changement de conformation de la forme pré-pore vers la forme pore et que les ligands EF et LF passeraient au travers le pore pour entrer dans le cytoplasme. Cependant, le diamètre du pore est environ dix fois inférieur à celui des ligands (10 Å contre 100 Å). Un processus de folding/unfolding a été proposé mais demeure controversé.
Afin d'identifier le processus de passage des facteurs EF et LF dans le cytoplasme, nous avons déterminé par cryo-microscopie électronique combinée avec l’analyse d’image les structures tridimensionnelles des complexes formés par PA et LF aux étapes prépore et pore. Par la suite, une étude complémentaire par dynamique moléculaire nous a permis de modéliser à haute résolution les différentes interactions qui ont lieu au sein du complexe.
La structure 3D du complexe prépore combiné à 3 LF a été déterminée à une résolution de 14 Å. Nous avons aussi calculé une structure préliminaire du complexe pore également combiné à 3 LF Celles-ci n’ont jamais été résolues auparavant et leur connaissance permet d’envisager l’étude en profondeur du mécanisme infectieux de l’Anthrax in vivo. / The anthrax toxins are part of the A-B toxin family in which the B moiety binds to the cell membrane allowing subsequent translocation of the A moiety. In the case of anthrax, the B moiety consists of the Protective Antigen (PA), and the A moiety is composed of the two proteins Edema Factor (EF) and the Lethal Factor (LF). After being recruited by the cell receptors (CGM2 or TEM8), PA organizes itself into a heptamer. It can bind up to three ligands (either EF or LF) before being endocytosed. Current models suggest that the decrease of pH inside the endosomes allows a conformational change of PA from a prepore form to a pore form that allows the EF and LF ligands to pass through the pore and enter the cytoplasm. However, the pore diameter is about ten times smaller than the diameter of the ligands (10Å versus 100Å). A process of ligand folding / unfolding has been proposed, but remains controversial.
To identify the mechanism by which EF and LF enter the cytoplasm, we have used cryo-electron microscopy and three-dimensional image analysis to determine the 3D structure of the PA-LF complexes in the pre-pore and pore conformations. Then, we used molecular dynamics to modelise at high resolution the different interactions that occur within the complex.
The 3D structure of the pre-pore complex bound with three LF ligands has been determined at 14Å resolution. We also calculated a preliminary structure of the LF-bound pore complex. These structures have never been reported before. They provide the necessary information to study in depth the mechanism of anthrax infection in vivo.
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Étude structurale conformationnelle des toxines de l’anthrax par cryo-microscopie et dynamique moléculaireFabre, Lucien 01 1900 (has links)
Les toxines de l’anthrax font partie de la famille des toxines A-B dans laquelle la moitié B se fixe à la membrane de la cellule permettant par la suite la translocation de la moitié A. Dans le cas de l’anthrax, la moitié B est représentée par le Protective Antigen (PA) et la moitié A par les deux protéines Edema Factor (EF) et Lethal Factor (LF). Après le recrutement par les récepteurs cellulaires (CMG2 et TEM8), PA s’organise en heptamère. Il peut fixer jusqu'à 3 ligands (EF et LF) avant d'être endocyté. Les modèles actuels de PA suggèrent que la baisse de pH à l’intérieur des endosomes permet un changement de conformation de la forme pré-pore vers la forme pore et que les ligands EF et LF passeraient au travers le pore pour entrer dans le cytoplasme. Cependant, le diamètre du pore est environ dix fois inférieur à celui des ligands (10 Å contre 100 Å). Un processus de folding/unfolding a été proposé mais demeure controversé.
Afin d'identifier le processus de passage des facteurs EF et LF dans le cytoplasme, nous avons déterminé par cryo-microscopie électronique combinée avec l’analyse d’image les structures tridimensionnelles des complexes formés par PA et LF aux étapes prépore et pore. Par la suite, une étude complémentaire par dynamique moléculaire nous a permis de modéliser à haute résolution les différentes interactions qui ont lieu au sein du complexe.
La structure 3D du complexe prépore combiné à 3 LF a été déterminée à une résolution de 14 Å. Nous avons aussi calculé une structure préliminaire du complexe pore également combiné à 3 LF Celles-ci n’ont jamais été résolues auparavant et leur connaissance permet d’envisager l’étude en profondeur du mécanisme infectieux de l’Anthrax in vivo. / The anthrax toxins are part of the A-B toxin family in which the B moiety binds to the cell membrane allowing subsequent translocation of the A moiety. In the case of anthrax, the B moiety consists of the Protective Antigen (PA), and the A moiety is composed of the two proteins Edema Factor (EF) and the Lethal Factor (LF). After being recruited by the cell receptors (CGM2 or TEM8), PA organizes itself into a heptamer. It can bind up to three ligands (either EF or LF) before being endocytosed. Current models suggest that the decrease of pH inside the endosomes allows a conformational change of PA from a prepore form to a pore form that allows the EF and LF ligands to pass through the pore and enter the cytoplasm. However, the pore diameter is about ten times smaller than the diameter of the ligands (10Å versus 100Å). A process of ligand folding / unfolding has been proposed, but remains controversial.
To identify the mechanism by which EF and LF enter the cytoplasm, we have used cryo-electron microscopy and three-dimensional image analysis to determine the 3D structure of the PA-LF complexes in the pre-pore and pore conformations. Then, we used molecular dynamics to modelise at high resolution the different interactions that occur within the complex.
The 3D structure of the pre-pore complex bound with three LF ligands has been determined at 14Å resolution. We also calculated a preliminary structure of the LF-bound pore complex. These structures have never been reported before. They provide the necessary information to study in depth the mechanism of anthrax infection in vivo.
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Proposta de protocolos de segurança para a prevenção, a contenção e a neutralização de agente agressor bioativo em incidentes bioterroristas e estudo por docking molecular do fator letal do Bacillus anthracis (Antraz)Negré, Walkmar Silva 29 October 2010 (has links)
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Previous issue date: 2010-10-29 / For centuries, infectious agents have been used as weapons in armed conflicts. In 1972 the Biological Weapons Convention prohibited the creation and stockpiling of biological weapons. However, some countries continued to research and develop these weapons. Proof of this fact was the crash in 1979 in a military factory in the USSR, where Bacillus anthracis were dispersed. Biotechnology in a globalizing world facilitates and contributes not only to the development of weapons programs of regular armies, but also to terrorist groups. Examples of such this are the contamination by the bacterium Salmonella typhimurium by a religious fanatic group that in 1984 poisoned 751 people in the U.S., and the bacterium Bacillus anthracis spores mailed in the U.S. to several people during 2001 and 2002, immediately after the attacks of September 11th. A biological weapon is of extreme difficult detection by security equipment. Most infectious agents are present in almost every continent, making it easier to obtain. The production is cheap and it is easy to carry, being a small amount enough to reach very large area and thousands of people. It is an invisible weapon, odorless and causes symptoms unknown to most physicians. So, given this background, in this master thesis we attempt to demonstrate the reality of the threat of a biological weapon based on Anthrax as the biological agent used as a weapon of mass destruction. Based on this study, we show the fragility of the state system for dealing with such incidents, and we propose security protocols in order to regulate what should be done in time of crisis, defining its management and streamline the decision-making. Finally, using the technique of molecular docking, we also studied the lethal factor of anthrax, and proposed the compound 1-Phenylsulfonyl-2-propanone (DARXOJ, C9H10O3S) as a good candidate to inhibit its effects. / Há séculos agentes infecciosos são utilizados como armas em conflitos bélicos. Em 1972 a Convenção sobre Armas Biológicas proibiu a criação e armazenamento de armas biológicas. No entanto alguns países continuaram a pesquisa e o desenvolvimento dessas armas. Prova desse fato foi o acidente em 1979 em uma fábrica militar na URSS, onde foram dispersos esporos de Bacillus anthracis. A Biotecnologia no mundo globalizado facilita e contribui não apenas aos programas de desenvolvimento de armas dos exércitos regulares, mas também aos grupos terroristas. Exemplos disso são a intoxicação pela bactéria Salmonella typhimurium por um grupo fanático religioso que em 1984, nos EUA, intoxicou 751 pessoas, e os esporos da bactéria Bacillus anthracis enviados pelo correio para várias pessoas em 2001 e 2002, imediatamente após os atentados de 11 de setembro nos EUA. Uma arma biológica é muito difícil de ser detectada por equipamento de segurança. A maioria dos agentes infecciosos está presente em quase todos os continentes, o que facilita a sua obtenção. A produção é barata e simples de transportar, podendo atingir com pequena quantidade área muito grande e milhares de pessoas. É uma arma invisível, inodora e que provoca sintomas desconhecidos pela maioria dos médicos. Em face desse panorama, neste trabalho procuramos demonstrar a realidade da ameaça de uma arma biológica e elegemos o Antraz como agente biológico utilizado como arma de destruição em massa. Neste estudo, mostramos a fragilidade do sistema estatal para lidar com este tipo de incidente, e propomos protocolos de segurança com o objetivo de regular os procedimentos no momento de crise, definindo o gerenciamento para melhorar e otimizar as tomadas de decisões. Finalmente, por meio do uso da técnica de docking molecular, também estudamos o fator letal do Antraz, e propusemos o composto 1-Fenilsulfonil-2-propanona (DARXOJ, C9H10O3S) como um bom candidato a inibir os seus efeitos.
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