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Dissertações em Química Medicinal e Modelagem Molecular (Mestrado) - PPGQMMM/ICS

URI Permanente para esta coleçãohttps://repositorio.ufpa.br/handle/2011/14431

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Acesso aberto (Open Access)
Simulação computacional do mecanismo catalítico da enzima catecol o-metiltransferase
(Universidade Federal do Pará, 2017-02-16) SILVA, Edson Leandro de Araújo; SILVA, Jerônimo Lameira; http://lattes.cnpq.br/7711489635465954; https://orcid.org/ 0000-0001-7270-1517
Methyl transfer reactions are very important in biological systems, the enzyme catechol O-methyltranferase catalyzes a transfer reaction of a methyl group of the co-substrate S-adenosylmethionine to dopamine. This disease is related to a Parkinson's disease that is a neurodegenerative disease that affects 7 to 10 million people of the world population, mainly a parcel over 60 years. Due to the importance of the reaction catalyzed by this enzyme, computational tools in conjunction with quantum mechanics methods were used to study the mechanism of reaction of the methyl transfer of S-adenosylmethionine to dopamine. In this study, the presence or not of Mg2+ in the reaction and changes in dopamine structure for catechol and phenol were taken into account in order to propose a quantum region more suitable for future non-enzymatic simulation work. The methods used in the PM6 semi-present method, the ab initio DFT and the MP2 correlation. The methods used include PM6 semiempirical method, ab initio DFT and perturbation MP2, where the first method was highlighted in the description of all reactions studied. The reaction with the catechol in the solvent had the following values of energy barriers: 18.62 kcal/mol (PM6); 9.91 kcal/mol (DFT); 14.44 kcal/mol (MP2). The presence of the Mg2+ ion in the same reaction with the catechol showed the following energy barrier values: 24.55 kcal/mol (PM6); 15.99 kcal/mol (DFT); 17.39 kcal/mol (MP2). The PCM solvation model was used to study a reference reaction in the enzymatic system and to analyze how energy barriers of the reaction in water and with barriers obtained in the gas.
Acesso aberto (Open Access)
Estudo do mecanismo conformacional da proteína 3-hidroxi-3- metilglutaril Coenzima A Redutase (HMGR) com as estatinas e substrato através de Dinâmica Molecular, PCA e Energia Livre
(Universidade Federal do Pará, 2017-08-03) COSTA, Clauber Henrique Souza da; SILVA, Jerônimo Lameira; http://lattes.cnpq.br/7711489635465954; https://orcid.org/0000-0001-7270-1517
Cholesterol is a substance of paramount importance for all animals. However, its high level in the human body is linked to the two major diseases that kill the world: ischemic heart disease and stroke. One of the synthetic drugs used in the treatment of hypercholesterolemia are statins, inhibitors of 3-hydroxy-3-methylglutaryl Cozyme A reductase (HMGR), which act primarily on the liver by inhibiting a conversion of the HMG-CoA substrate into mevalonic acid, which is the metabolite Cholesterol precursor. Studies Molecular Dynamics (MD) combined with Principal Component Analysis (PCA) were performed to verify the mechanism of the changes in the Cterminal Flap domain form (residues His861, Leu862, Val863, Lys864, Ser865 and Hys866) after binding substrate and efficient statins in inhibiting the HMGR enzyme. A total of 500 ns of MD simulation time were performed in this study. Binding Free Energies calculations were used, which estimate that the structural mechanism of the Flap is related to an action of the HMGR protein, since domain control or access to the active site of the enzyme. The results also show that the structural modification of Flap increases the energy contribution of the system by involving larger interactions with catalytic residues and, consequently, an ability to inhibit cholesterol production, as observed for the catalytic His866, which has a very favorable contribution when the Flap is in the closed state, with energy of -14,802 Kcal/mol, and when the Flap passes to the open state the contribution is less favorable, with -1,022 Kcal/mol, for 1 inhibitor, showing that in the closed state the catalytic residue is directly involved and contributes in a favorable way to the system, leading to a better understanding of the conformational changes of HMGR after a binding of statin derivatives and HMG-CoA substrate.
Acesso aberto (Open Access)
Planejamento, síntese e aplicações de derivados naftosalicílicos como antioxidantes
(Universidade Federal do Pará, 2017-08-30) BARROS, Valéria Araújo; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/ 0000-0003-4072-7573
Salicylate derivatives are successfully applied as analgesics, antipyretics, anti-inflammatories and in cancer prevention, especially rectal colon. They reduce the risks of many diseases associated with elderly. However, adverse effects related to gastrointestinal events are always associated to its main constituent acetylsalicylic acid. These aspects are linked to their chemical stability and affinity for some biological receptors. The aims of this work are the design, synthesis and applications of naphthalene-salicylic derivatives as antioxidants. Thus, a theoretical study of the studied compounds was carried out. Calculations of electronic properties such as frontier orbitals HOMO-LUMO, ionization potential (IP), bond dissociation energy of phenolic moiety (BDEOH), and spin density contributions were performed by using density functional theory (DFT) at the B3LYP/6-31G (d, p) level of theory on Gaussview and Gaussian computational packages. Some of these compounds were synthesized by using classical methods. The theoretical results showed that both additional hydroxyl or substitution on benzene ring for naphthalene increase the antioxidant capacity in the same values with small dissimilarities among acid, ester, and amide derivatives. A synergistic effect was observed when both are used together, producing the most potent molecules. In addition, spin density calculations indicated a regioselective pathway can be gotten from monohydroxylic derivatives, with high possibility of in vivo generating of dihydroxy derivatives mainly at the para position relative to the phenolic group, through enzymatic or non-enzymatic reactions. Finally, the replacement of the naphthalene ring instead of the benzene ring increases both reactivity and chemical stability for the quinone-type intermediates, explaining how these compounds will play a role in the preventive mechanisms and way treatment of cancer. Anti cancer and anti-inflammatory activities are being performed for some of the synthesized compounds.
Acesso aberto (Open Access)
Atividade citoprotetora e cicatrizante da espécie Conocarpus erectus l em lesões gástricas induzidas em ratos Wistar adultos
(Universidade Federal do Pará, 2017-09-06) VIEIRA, Vaneza Rodrigues; MELLO, Vanessa Joia de; http://lattes.cnpq.br/9437589201689717
The pharmacological research has been aimed at the knowledge of regional folk medicine, in order to establish the scientific bases of their respective pharmaceutical products’ effectiveness. Among the many natural sources used in our region are the species Conocarpus erectus L, popularly known as the "mangrove bud", belonging to the Combretaceae family. Different parts of the plant such as leaves, stems, fruits and flowers have their biological activity studied, among them the anticancer and antimicrobial effects. Ethnopharmacological reports obtained in the region of Salinópolis - PA also described a potential use in digestive disorders. Although a great advance in the drug therapy used in the cases of gastric ulcerationhas been made, it is important to carry out studies that prove its validity. This work aims to verify the cytoprotective activity and cicatrizing activity of the lyophilisatebark teaobtained by decoction of the species Conocarpus erectus L (LCE) in acute and chronic gastric lesions. The methodologies for evaluating the cytoprotective effect were acute lesions inducted by indomethacin and ethanol, while the cicatrization effect was evaluated by chronic acetic acid-induced lesions in adult Wistar rats. The intragastric pH variation was measured by the pylorus ligament assay. The lyophilizate’santioxidant activity was evaluated by the DPPH assay, as well as the lipid perioxide levels’ that were evaluated by the TBA-RS method in chronic lesions induced by acetic acid 5 and 10%. The results showed cytoprotective activity of LCE by the indomethacin induction model reduced the ulceration index (IU) in the treated group by 51,49%, omeprazole group by 51,33% and sucralfate group by 71,28%, all of them when compared to the controlled group. On the model of ethanol LCE’s induction, the area affected was reduced by 90.94%, and in the sucralfate’s induction group, by 75.88% when compared with the controlled group. The LCE’s healing effect reduced gastric lesions to 5% in 80.11%, while the on omeprazole group to 52.75% and the sucralfate group reduced to 66.33%, whereas in the 10% gastric lesionsthe LCE group reduced 72.11%, the omeprazole 57.47%, and the sucralfate group 43.77% (p>0,05Anova, post testDunnett'sand Turkey). The LCE treatment showed an increase of 39% onintragastric pH when compared to control (p>0,05Anova, post testDunnett's e Turkey’s) and did not statistically showed any different from the omeprazole group by the model of pylorus ligation. The LCElyophilizate’santioxidant effect was confirmed by the DPPH assay, as it was diluted in 10x, 50x and 100x with a percentage of 67.65% ± 0.52, 73.22% ± 0.17 and 72.70% ± 1.39, respectively, when compared to the ascorbic acid antioxidant of 33,74% (AA) like this (p <0.05, Anovapost testDunnett). A lipid peroxidation evaluated in the lesions obtained by the 5%-acetic-acid-induction model showed that the average MDA levels in the nave group, controlled group and treated group LCE were 0.492 ± 0.0849, 1.579 ± 0.219, and 0.399 ± 0.092, respectively, showing that the LCE-treated group was able to reduce lipid peroxidation by 74.73% in comparison to the controlled group (p<0,05 Anovapost testDunnet) and it did not statisticallydiffer from the nave group. On the 10%-acetic-acid-model the average level of malonaldehyde in the nave group, controlled group and the LCE-treated group was 0.628 ± 0.042, 1.567 ± 0.234 and 0.441 ± 0.12, respectively. The LCE treated group managed to reduce by 71.85% the lipid peroxidation caused by acetic acid induced lesions when compared to the control group (p <0.05 Anovapost testDunnet).These results confirm the cytoprotective and cicatrizing effects of LCEand suggest possible action mechanisms associated with its antioxidant potential, as well as possible acid secretion inhibition.
Acesso aberto (Open Access)
Estudo teórico das interações entre inibidores da inha, enoil acp redutase do mycobacterium tuberculosis
(Universidade Federal do Pará, 2017-09-29) BAHIA, Jeann Ricardo da Costa; CARNEIRO, Agnaldo da Silva; http://lattes.cnpq.br/8915348778787525
Isoniazid is the oldest, cheapest and most effective synthetic prodrug of the first line of treatment for Tuberculosis. It should be activated by the Mycobacterium tuberculosis catalase-peroxidase, KatG, which produces an isonicotinoyl-NADH adduct, INNADH, which targets the M. tuberculosis Enoyl-ACP reductase protein, InhA, in order to disrupt the synthesis chain of mycolic acids. Resistance to isoniazid alone or in combination with other drugs is one of the most common forms of resistant tuberculosis and poses a threat to the control of this disease. In this context, triclosan (TCL) appears as an alternative inhibitor of the synthesis of mycolic acids, since it is also specific to InhA. This study aims to evaluate the interactions of inhibitors of InhA through Molecular Dynamics Simulation (DM) and propose possible new inhibitors for this enzyme. The system used in this work was captured from the database PDB, code 4TRO. Eight ligands, NADH, INNADH, and the TCL, P31, P41, P52, P61, P72 and P80 derivatives were evaluated. In the lower region of the active site of InhA were more frequent π charge stacks made by PHE41 and PHE97 with the ligands NADH, INADH, P80, P31, P72, however P41 made a hydrogen bond (LH) with PHE41. In the central region of the active site, residues such as A GLY96, SER20 and ILE21 did LH with NADH, INNADH, P31, P41 and P80. In relation to the upper region of the InhA site. The PHE149 performed EC-π with the INNADH and P41. Already in P31 was an LH with this residue and in P80 the energies are favorable for interaction. The free energies of each system presented in descending order are INNADH (-72,038 kcal / mol), P80 (-45,841 kcal / mol), NADH (- 41,463 kcal / mol), P41 (-40,178 kcal / mol), P31 (-30.614 kcal / mol), p52 (-19.475 kcal / mol) and P61 (-12.297 kcal / mol). These results highlight P80 and P41 as promising candidates for M. tuberculosis mycolic acid synthesis inhibitors, since being an energy profile is competitive with the values shown by NADH.
Acesso aberto (Open Access)
Avaliação farmacológica da fração ácida do óleo de copaíba intercalada em hidróxidos duplos lamelares
(Universidade Federal do Pará, 2017-10-03) BARBOSA, Aline da Silva; QUEIROZ, Luana Melo Diogo de; http://lattes.cnpq.br/9775224837043003; https://orcid.org/ 0000-0001-5036-5639
Copaiba oil is traditionally used in the Amazon region of Brazil for pharmacological purposes as pain and inflammation. The acidic fraction of copaiba oil (FAOC) consists of diterpenes and, among them, excels copalic acid as major component, being endowed with anti inflammatory activity in vitro. In addition to the research for new active principles, there is also interest in management models that optimize the action of drugs. For this, an alternative is the controlled release of drugs, which can be obtained by the intercalation of these in Lamellar Double Hydroxides (HDLs). Thus, this study aimed to evaluate the antinociceptive and anti-inflammatory activity of the FAOC and FAOC intercalates in HDL (FAOC-HDL) in vivo models of nociception and inflammation. Male (Mus musculus) mice (4 to 6 weeks old, weight 25-35g) were divided into groups (n = 6) and treated orally (0.1mL/10g), with negative control (vehicle), HDL, FAOC, FAOC-HDL, and positive control, 1h, 24h and 48h before each test. First, was determined the median effective dose (DE50) and then the experimental models of acetic acid-induced abdominal contraction, formalin test, croton oil induced ear edema, carrageenan-induced paw edema test and peritonitis induced by carrageenan. The ED 50 found was FAOC (98 mg/kg) and FAOC-HDL (222.9 mg/kg). After 1 h of treatment, FAOC (98 mg/kg) and FAOC-HDL (222.9 mg/kg) significantly inhibited the number of abdominal writhing respectively in 49.99% (22,67± 1,56) and 56,99% (19,5 ± 2,69), the paw licking time in the formalin test was 28.93% (113.6 ± 12.45) and 60.79% (62.67 ± 11, 02) in the second phase of the test, development of ear edema in 25.59% (2.53 ± 0.21) and 47.65% (1.78 ± 0.20) and development of paw edema in the 2nd and 3rd hour of the test and the migration of total leukocytes by 73.17% (1.95 ± 0.38) and 75.69% (1.77 ± 0.28) and neutrophils in 62.82 (1.61 ± 0.31), 91.0% (0.39 ± 0.10) in the peritonitis. There was also a significant effect on treatment with FAOC-HDL (222.9 mg/kg) after 24 h of treatment, inhibiting the number of abdominal writhes in 58.34% (20.0 ± 3.97), lambda time of the paw in the formalin test 33.97% (98.83 ± 13.64), the development of ear edema in 57.05% (2.47 ± 0.36) and the development of paw edema in the 3rd hour of the test in 30.28%, (0.27 ± 0.02). Thus, the results obtained show antinociceptive and anti-inflammatory effect of the FAOC and, underpinning this effect by the controlled release of FAOC intercalates in HDL.
Acesso aberto (Open Access)
Investigação computacional de bromo-ariloxi-2-acetamida etil-benzimidazólicos como inibidores não-peptídicos da proteinase cruzaína de trypanosoma cruzi
(Universidade Federal do Pará, 2017-11-17) FERREIRA, Fábio Jorge de Nazaré; ALENCAR, Nelson Alberto Nascimento de; http://lattes.cnpq.br/3035968396241810; https://orcid.org/ 0000-0002-5763-7024; CARNEIRO, Agnaldo da Silva; http://lattes.cnpq.br/8915348778787525
Chagas’ disease is an infection caused by the Trypanosoma Cruzi flagellated protozoan transmitted by insects (gnat) known in Brazil as “barbeiro” (barber). In the Amazon region, studies have shown that oral contamination has been frequent. The only available drugs for the treatment of Chagas’ disease - Benzonidazole (Rochagan R , Roche) and Nifurtimox (Lampit R , Bayer) - have shown limited efficiency and severe side effects. Cruzain is an enzyme present at all stages of the life cycle of T. cruzi and is the most abundant of the family of papain cysteine proteases found in the parasite, being a promising enzymatic target for the design and development of inhibitors against the disease. Non-peptidic non covalently bound to the enzyme were synthesized and evaluated biologically in vitro and in vivo by Ferreira et al. (2014) analogs of the 8D (or B95) leader compound (crystallographic), yielding a series of active compounds, of which the most powerful are: 8K, 8L and 8R. This work investigated the potential interactions and energies of the cruzain (PDB code: 3KKU) complexed with these four ligands by means of computational tools in order to help elucidate their potential inhibition activity in this enzyme. The computational protocol (parameters, topologies, coordinates, minimizations, thermalizations and productions) was the same for each system. In the final stage of molecular dynamics (MD) production, each system was simulated for a period of 100 ns, to which the mean square deviation (RMSD) stability values of the enzyme and the marked change in 8L ligand conformation were analyzed. The quality of the simulation was also evaluated through potential, kinetic and total energy, volume and temperature graphs. Interactions of hydrogen bonds of the ligands with some amino acid residues belonging to the catalytic site were analyzed. The interaction between the ASP161 and the 8R ligand is emphasized, being ratified by the energy decomposition by residue showing that ASP161 has the best contribution. In terms of binding free energy, the ∆Gtotal follows the experimental trend, pointing the 8R ligand as the most favorable to the reaction having a theoretical value of -30.04kcal.mol−1. This spontaneity is ratified by means of the values obtained with the SIE method, whose theoretical value was -7.54 kcal.mol−1. The results of this work should favor the optimization of compound 8R or development of a series of analogs of this molecule in order to be used as a possible drug for the treatment of Chagas’ disease.
Acesso aberto (Open Access)
Síntese, intercalação, caracterização estrutural e análise biológica de nanopartícula carreadora de ácido kójico
(Universidade Federal do Pará, 2017-11-30) DIAS, Amarílis Aragão; SILVA, Jerônimo Lameira; http://lattes.cnpq.br/7711489635465954; https://orcid.org/ 0000-0001-7270-1517; ALVES, Claudio Nahum; http://lattes.cnpq.br/8315600067791313; https://orcid.org/ 0000-0001-6576-4229
Intercalation of species with pharmacological activity in layered double hydroxides (LDHs) is a growing field in academic and industrial research, these compounds are capable of promoting the controlled release of drugs. In this work we merge the kojic acid in LDH nanoparticles of Mg2+/Al3+ by co-precipitation method. This substance has many applications in various fields of research, however it is easily susceptibile to photo-oxidation which causes organoleptic and chemical modifications of its structure. Recently kojic acid was introduced as a potent inhibitor of Leishmania cultures, we believe that the particular properties of HDL, such as photoprotection, and stabilization of the interleaved facilitate the production of a material resistant to possible applications for health. All samples were prepared by the co-precipitation method, were further characterized by X-ray diffraction, Raman, IR, UV-vis spectroscopy, thermogravimetry, and biological evaluations of Leishmania cultures. Our results demonstrate that HDL has 53.018% AK intercalated kojic acid and is able to withstand high temperatures, in addition to having an anti-leishmania potential.
Acesso aberto (Open Access)
Planejamento, síntese e avaliação dos derivados da edaravona quanto à atividade antioxidante
(Universidade Federal do Pará, 2018-03-28) AIRES, Wanessa Castilho; OLIVEIRA, Karen Renata Matos; http://lattes.cnpq.br/3032008039259369; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/ 0000-0003-4072-7573
Edaravone is a commercial drug released on the Japanese Market, indicated in the treatment and prevention of ischemic stroke. Its action is due to its scavenger properties of free radical released in the ischemia. However, its use may lead to a kidney toxic effect. Therefore, in this work, a new bioisostere derivative from Edaravone was proposed, by the change of a pyrazolone ring for an indolone. Antioxidant properties was determined through computational methods. Calculations were undertaken in the software Gaussian, through the B3LYP method, with the set of bases 6-31G (d, p). Antioxidant activity was predicted from HOMO, LUMO, Gap, Ionization potential (IP) and Bond dissociation energy (BDE). Results indicate analogous compounds showed higher ClogP values compared to Edaravone, which means higher facility to pass through biological barriers, with higher liposoluble properties. Edaravone derivative, called Imidazone, also showed higher antioxidant potential than Edaravone. Methyl group in second position of heterocyclic ring was essential to more stable resonance structures formation to semiquinone form. All new derivatives proposed were extremely promising with antioxidant capacity superior to Edaravone.
Acesso aberto (Open Access)
Investigação teórica da síntese de mdma a partir do safrol e estudo da atividade de anfetaminas via qsar
(Universidade Federal do Pará, 2018-03-28) COSTA, Miony Carolina Cardoso; MACEDO, Luiz Guilherme Machado de; http://lattes.cnpq.br/3809730482457606; https://orcid.org/ 0000-0002-8257-5662
Amphetamine are drugs that stimulate the central nervous system. They cause increase of physical and psychic capacities, and they are sympathomimetic substances that have the basic chemical structure of beta phenethylamine. It is also a drug that can be produced from easily accessible reagents. Its synthesis is most often done in low cost clandestine laboratories and its consumption is a public health problem. In the present work the MDMA synthesis reaction from Safrol was investigated. This that occurs in two steps: first a halogenhydride addition, followed by a nucleophilic substitution. The thermodynamic properties of the Safrol reaction were investigated, and the NMR, UV-visible, IR spectra of the reagent, intermediate and product are shown. An high yield alternative route of synthesis is also suggested. For the electronic structure calculations, the DFT method was used with different functionals and basis sets in order to obtain results with chemical accuracy (CBS-QB3) and minimal deviation with respect to the experimental values. Finally, a study of the QSAR of 30 amphetamine derivatives and the MDMA molecule was carried out, since according to the literature it has biological activity, and a R2 (correlation coefficient square) of 0.886 and Q2 (of the cross-validation correlation coefficient) near 0.74, these two values confirm the high variability and predictability of the model.
Acesso aberto (Open Access)
Intercalação de ácido caféico em hidróxido duplo lamelar pelo método de troca iônica: novas formulações leshimanicida
(Universidade Federal do Pará, 2018-03-28) VALENTE, Jeovan do Espirito Santo; MENESES , Carla Carolina Ferreira; http://lattes.cnpq.br/3165259533988836; ALVES, Claudio Nahum; http://lattes.cnpq.br/8315600067791313; https://orcid.org/ 0000-0001-6576-4229
The drug delivery systems shows several advantages when compared with traditional release systems, such as allowing the employment of lower concentrations of drug, having greater efficiency, and minimizing side effects. The improvement of drug delivery depends strictly on the choice of and adequate support allowing to effectively controlling the drug release. Thus, the use of inorganic hybrid materials, such as layered doubles hydroxides (LDH) is of great interest because of their properties. Caffeic acid (CA), coming from several natural sources, exhibits different biological activities with featured for the leishmanicidal activity. In this work, the ion exchange methodology was used for the intercalation of Caffeic acid (CA) molecules between the LDH/MgAl layers. This, in order to obtain more stable AC formulations compared to free drug. Physico-chemical characterizations were used for analysis of the structure and morphology of the hybrid compounds obtained, such as XRD, FT-IR and SEM.
Acesso aberto (Open Access)
Aspectos teóricos da interação entre compostos cefalosporínicos e a Proteína 5 de Ligação à Penicilina de Escherichia coli usando Dinâmica Molecular
(Universidade Federal do Pará, 2018-08-04) OLIVEIRA, Amanda Ruslana Santana; BARROS, Carlos Augusto Lima; http://lattes.cnpq.br/8902921733540173
Escherichia coli is an anaerobic Gram-negative bacillus that naturally inhabits the intestines of mammals. The diseases arise when the bacteria reaches other organs of our body, causing infections, mainly in the urinary tract of women, due to the proximity of the female urethra with the anus. Antibiotics were used in the treatment of these infections, such as antibiotics of the cephalosporin class, which are the group with the highest number of β-lactam antibiotics in clinical use. These compounds can inhibiting the enzymatic function of Penicillin-Binding Proteins (PBP), which is responsible for the final step of biosynthesis of peptidoglycan, an essential component for the survival of bacteria. In this work, the antimicrobial compounds cefoxitin, cefuroxime, cefotaxime, cephalothin, cefixime, cefmetazole and 7- aminocephalosporanic acid were chosen based on experimental studies of biological activity in the fight against the opportunistic Gram-negative pathogen Pseudomonas aeruginosa, to be studied theoretically through Molecular Dynamics simulations, binding free energy calculations, and interaction energy per residue, for the determination of their potential biological activity in inhibiting the enzymatic function of E. coli specific PBP, Penicillin Binding Protein 5 (PBP5), therefore its inhibition leads to cell death. More favorable binding free energies were obtained for the cefoxitin (crystallographic), cephalothin and cefuroxime ligands, -31.471 Kcal/mol, - 34.225 Kcal/mol and -35.085 Kcal/mol, respectively, and it was observed that the catalytic residues Ser44 and His216 presented more favorable energy contributions to the system formed by the cephalothin ligand. Thus, it was suggested that cephalothin has excellent potential for inhibition of the enzymatic function of E. coli PBP5, responsible for the final phase of transpeptidation of the peptidoglycan layer.
Acesso aberto (Open Access)
Planejamento e desenvolvimento de análogos da nitazoxanida
(Universidade Federal do Pará, 2018-09-25) FERREIRA, Lanalice Rodrigues; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Nitazoxanide is a molecule applied in the antihelminthic therapy and has a broad spectrum as antiparasitic agent. In biological studies by using this molecule, new therapeutic targets and good results were found. Nevertheless, it still has some chemical and pharmaceuticals problems which need improvements. The objective of the study is the design and development of stable nitazoxanide derivatives using molecular modeling and organic synthesis approaches. All calculations of electronic properties such as frontier orbital (HOMO and LUMO), ionization potential (IP) and electronic affinity (AE), electrostatic potential map (MPE) were performed using the Gaussview e Gaussian. The theoretical study of nine amino-nitro-azolic derivatives, an essential moiety of nitazoxanide pharmacophore, was performed using the DFT/B3LYP/6-31G (d,p) method and showed that thiophene ring modifications can reduce the redox potential changing the reactivity and toxicity. All derivatives have better electrophilic properties and depends on the presence of nitro group. These results are confirmed by maps of electrostatic potentials and can indicated the most reactive regions that probable act on electrophilic attacks. Physicochemical parameters of nitazoxanide analogues were also evaluated using the DFT/B3LYP/6-31+G (d,p) method. A significant increase in the electron donating capacity for these new molecules from the HOMO, LUMO and GAP values was observed. An additional nitro group on ring structure beget compounds that have great stability and electron-accepting capacity. This electronic property is essential for biological activity on nitro compounds. The electrostatic potentials for nitazoxanide and its related analogues show the significant negative charge density on the nitro region. In addition, a conformational analysis of nitazoxanide, tizoxanide and a nitazoxamide derivatives was performed. The lower conformer of nitazoxanide agrees with the crystallographic structure. The more stable structures of the derivatives are related to their conformational similarity. The nitazoxanide molecule and three other derivatives have been synthesized and are available for biological evaluation on future works.
Acesso aberto (Open Access)
Planejamento e síntese de novos derivados da associação molecular benzonidazol e metronidazol
(Universidade Federal do Pará, 2018-09-25) COSTA, Fernanda Menezes; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Chagas disease is caused by protozoan Trypanosoma cruzi, still has high contagion rates in present days, especially in the Amazon region. After contamination, the infective cycle of Chagas disease has two phases: acute and chronic. The acute phase is, in majority of cases, asymptomatic and efficiently treated, however the chronic phase is symptomatic and has proved not efficient treatment. There is only one available medicine, the generic benznidazole or Rochagan®, distributed free of charge, and it must be administered for 60 days, approximately. However, benznidazole has low efficiency, being effective only on acute phase (asymptomatic). Besides that, the medicine use to cause severe side effects in clinical patients, producing in many times the treatment rejection. The molecular modeling has become an important tool on new drugs design, using the DFT method to evaluate of the new potent molecules. Thereby, the main goal of this work was to design new derivatives by using molecular modifications of benznidazole and metronidazole aiming to reduce their redox capacity. With this purpose, a theoretical study was performed of two benznidazole derivatives through molecular association and chain increase. From the theoretical study, this molecular association between benznidazole and metronidazole molecules can develop a less toxic new derivative of than benznidazole. Both designed derivatives were synthesized on laboratory using the classics methodologies of electrophilic and nucleophilic substitution, esterification, alkylation and nitration. According to their HOMO, LUMO, ionization potential, and electron affinity values, it was possible observe that the nibendazole 1 and nibendazole 2 compounds have a lower redox capacity when compared to benznidazole. The GAP values showed that the derivatives are less reactive than benznidazole. The HOMO and LUMO graphics, showed that the nitroimidazoles rings have high electron-withdrawing capacity as well as benzyl group has high electron-donating capacity. These properties change in accordance to methyl moiety or nitrogen positions on azolic ring of derivatives compounds.
Acesso aberto (Open Access)
Modelagem molecular de inibidores da enzima tirosinase
(Universidade Federal do Pará, 2018-12-21) MARTINS, Lucas de Sousa; SILVA, José Rogério de Araújo; http://lattes.cnpq.br/0925631339396542; https://orcid.org/0000-0003-2310-5107
The enzyme Tyrosinase (TYR), responsible for the catalysis of the early stages of melanogenesis in various organisms, is described in some groups. Among those that stand out: hyperpigmentation, melasma and skin cancer, in not melanoma forms and malignant melanoma. In general, dysfunctions are treated with depigmenting agents, TYR enzyme alerts. However, among them is the kojic acid (KA), marked side effects. Such phenomena make a TYR a model of biological development of drug prototypes. In the meantime, I investigated some TYR enzyme inhibitory genes, in particular AK and analogous plants, as well as a Tropolone and some benzaldehyde derivatives, structurally related to the natural substrates of TYR (L-Tyrosine and L-Dopa), as the Molecular Docking, Molecular Dynamics (MD), and the Linear Interaction Energy (LIE) method, used to calculate the free binding energy of the systems. Specifically application of Molecular Docking defined the mode of binding of the inhibitors in the TYR site, being possible to quantify how interactions occur in the systems. As the MD simulations, they exhibited the effect of the enzyme with different inhibitors and how they act when complexed with a TYR enzyme, using a copper dummy atom model. Thus, the results obtained by LIE were concordant with the experimental results, obtaining an R2 of 0.91 in a linear regression of LIE vs Experimental, and this allowed to analyze how Tropolona, KA, MOL2 and MOL3 interactions with the important to the active site of TYR. Thus, the results achieved at work contributed significantly to the achievement of inhibition of the TYR enzyme, helping to combat the evils caused by a cycle of melanin production in organisms.
Acesso aberto (Open Access)
Planejamento, Síntese, Avaliação das Propriedades Teóricas de orto-Regioisômeros Substituídos do Paracetamol
(Universidade Federal do Pará, 2018-12-28) MORAIS, Roberto Barbosa de; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Paracetamol is a clinically proven analgesic and antipyretic, which promotes analgesia by elevating the pain threshold and antipyretic through action in the hypothalamic center that regulates the temperature. Currently paracetamol is one of the medicines that is available in all the countries of the world in places related to health and can be acquired without prescription. Considered one of the most widely used drugs in the world as it is cheap and easy to access, it can also be used from birth to the elderly. Like non-steroidal anti-inflammatory drugs (NSAIDs) paracetamol is able to inhibit the synthesis of prostaglandins from arachidonic acid under specific conditions by inhibiting cyclooxygenase (COX). Although it is considered safe at therapeutic doses, Paracetamol has a toxicity attributed to one of its metabolic intermediates called N-acetyl-p-imine-benzoquinone (NAPQI), produced through enzymes present in cytochrome P450 (CYPE21). Thus, the objective of this present work is to plan, synthesize and evaluate possible antinociceptive and antipyretic activities of paracetamol analogues, ortacetamol and its derivatives in order to obtain a less toxic derivative. The calculations of electronic properties such as higher energy occupied molecular orbital (HOMO), lower energy unoccupied molecular orbital (LUMO), ionization potential (PI), phenolic bond dissociation energy (BDEOH) and spin densities were performed using the Gaussview and Gaussian 2009 packages. The values of the average values of BDENH, among others, are those that are observed with the quality of a heating cycle for the high speed with the possibility of a chelation defined by a hydrogen bond of the amide with the phenoxyl radical. Given the results it is possible that BDENH energy compounds may be less potent than hindering the action of CYP on oxidation to form toxic intermediates. A proposed chlorinated derivative was proposed and synthesized. It is in biological evaluation phase. Orthacetamol was more potent antioxidant than paracetamol. Experimental results are in aggrement with theoretical values. We conclude that ortcetamol may be a potentially safer bioactive candidate than paracetamol.
Acesso aberto (Open Access)
Usando a dinâmica molecular para avaliar o impacto que as mutações na protease do HIV-1 produzem na interação da proteína com o antirretroviral darunavir
(Universidade Federal do Pará, 2019-03-29) CUNHA, Karoline Leite; BARROS, Carlos Augusto Lima; http://lattes.cnpq.br/8902921733540173
The emergence of drug-resistant strains used in antiretroviral therapy grows alarmingly on a global scale. Antiretrovirals used in the treatment of first and second line HIV are the ones that most have case reports of resistant strains. Protease inhibitors are a class of antiretroviral drugs that play a key role in AIDS treatment regimens. In addition to the emergence of resistance to IPs used in the usual treatment regimens, Darunavir, a protease inhibitor used in therapeutic rescue treatment, is already reported in patients who already have failed initial treatment and proven resistance. The aim of this work is to evaluate, identify and quantify HIV-1 3UCB protease mutations, as well as to evaluate, through molecular dynamics simulations, the impact that mutations produce on the interaction of 3UCB and its darunavir ligand when compared to the native HIV-1 protease 4LL3 complexed to the same linker.The results obtained in this study showed that the 3UCB multi-resistant HIV-1 protease had a slightly more stable binding profile than the native HIV-1 protease complex 4LL3, with binding free energy results -68.77 and -64.62 kcal / mol, respectively.
Acesso aberto (Open Access)
Modelo experimental para indução de hemiparkinsonismo por 6-hidroxidopamina em primatas sapajus apella e avaliação das alterações motoras
(Universidade Federal do Pará, 2019-06-09) LEAL, Leon Claudio Pinheiro; KREJČOVÁ, Lane Viana; http://lattes.cnpq.br/2604693973864638; https://orcid.org/0000-0001-8016-5283; BAHIA, Carlomagno Pacheco; http://lattes.cnpq.br/0910507988777644; https://orcid.org/0000-0003-3794-4710
Parkinson's disease is currently the second most common neurodegenerative disease in the world, with a high incidence in North and South America and Europe, for more than 50 years we have not seen any revolutionary treatment for the disease and many aspects of its neuropathology that still remain without a concrete enlightenment, in this feeling the experimental model in primates approaches the human reality are invaluable value for the development of new therapies and elucidation on mechanisms related to the disease. The 6-hydroxydopamine model in primates is a model that mimics some motor symptoms characteristic of PD. The present study aimed to develop a protocol for the induction of HemiParkinsonism in Sapajus apella primates. Three Sapajus Apella monkeys, all adult males, were submitted to daily conditioning sessions using the positive reinforcement clicker technique for primate chair positioning. Concurrently, the staircase and Brinkman tray motor tests were performed to determine laterality by the manual preference and dominance attributes. After this period, two 6-OHDA induction protocols were performed, the first protocol was injected into 10 sites in the nucleus striatum and the second protocol was injected into 10 sites in the nigrostriatal pathways, one week after the injections were performed twelve weeks of clinical analysis . All animals learned the input and positioning behaviors in the chair in a minimum of 30 sessions using pure positive reinforcement. The results of the staircase test demonstrated that the animals presented laterality consistent with the assignments of manual preference and dominance. The Brinkman test, specifically, presented lower sensitivity for determination of the same attributes, despite being the most commonly used test. Clinical analysis revealed that the second induction protocol had more motor symptoms characteristic of PD. Induction by 6-OHDA in the nigrostriatal pathways has been shown to be a good induction method for treatment studies and for a better understanding of the disease.
Acesso aberto (Open Access)
Planejamento de inibidores da enzima 3-deoxy-D manooctulosonato 8-fosfato Sintase (KDO8PS): um novo alvo para tratamento de infecção bacteriana
(Universidade Federal do Pará, 2019-07-23) ARAÚJO, Jessica de Oliveira; SILVA, Jerônimo Lameira; http://lattes.cnpq.br/7711489635465954; https://orcid.org/0000-0001-7270-1517; LIMA, Anderson Henrique Lima e; http://lattes.cnpq.br/2589872959709848; https://orcid.org/0000-0002-8451-9912
Bacteria can be distinguished in two groups through the Gram technique, where Gram positive and Gram-negative bacteria can be differentiated, the main differences between these organisms being the structure of the cell wall, its components and its functions. More evidence has emerged of bacteria resistant to antibiotics, the case of Gram-negative bacteria is more worrisome due to the emergence of strains resistant to various antibiotics. Lipopolysaccharide (LPS) is a component of the outer membrane of Gram-negative bacteria responsible for toxic manifestations such as inflammation. 3-Deoxy-D-manno-octulosonate (KDO) is a site component of the inner core of LPS essential for its formation. The reaction for KDO production requires two substrates, phosphoenolpyruvate (PEP) and D-arabinose 5-phosphate (A5P), catalyzed by 8-phosphate synthase 3-Deoxy-D-mannoocobluconate (KDO8PS). This reaction is important because it plays a crucial role in the assembly of LPS. This enzyme is in two distinct forms as the dependence of the presence or absence of divalent metal ion in the active site. There are several inhibitors of KDO8P synthase, two were selected based on their inhibition constants (Ki), with BPH1, the most active among them with a value of 0.37 μM in KDO8P metal synthase independent in E. coli and BPH2 with value of 7.9 ± 1.6 μM for metal-independent KDO8P synthase in N. meningitidis, these K i values are approximately 2 to 3 times higher than the Km values for PEP that were also used in this work, in addition to a third hypothetical inhibitor that combines the main characteristics of the inhibitors already described in the literature. Molecular Dynamics, Molecular Dynamics and Free Energy of bonding with the methods MMGBA, MMPBSA, SIE and Energy decomposition by residue to analyze the coupling mode of these ligands and the PEP substrate were used. With the results obtained, we analyzed the main interactions of these ligands and the molecular behavior of both the ligands and the protein. Therefore, more favorable binding-free energy values were obtained for the complexes formed with the BPH1 linker with the three methods -96.07 Kcal / mol with MMGBSA, -107.09 Kcal / mol with MMPBSA and -13.53 with SIE and observed these complexes perform a greater number of effective interactions. Thus, it is suggested that the BPH1 linker has an excellent potential for inhibiting the catalytic activity of the enzyme KDO8P synthase responsible for the production of KDO, essential component of LPS for the formation of the outer membrane of Gram-negative bacteria.
Acesso aberto (Open Access)
Estudo teórico da reação de metilação da proteína lisina metiltransferase (pkmt)
(Universidade Federal do Pará, 2019-10-09) GOMES, Guelber Cardoso; LIMA, Anderson Henrique Lima e; http://lattes.cnpq.br/2589872959709848; https://orcid.org/0000-0002-8451-9912; SILVA, Jerônimo Lameira; http://lattes.cnpq.br/7711489635465954; https://orcid.org/0000-0001-7270-1517
Cancer is one of the main targets in academic research and its understanding is related to gene regulation through histone methylation. G9a protein is responsible for the methylation of histone 3 Lysine 9 (H3K9), which can perform one or two methylations on this specific residue. Thus, computational techniques were used to describe this reaction through QM/MM simulation using the techniques of SEP, PMF in the Dynamo program and the mechanism in the AMBER program with the methods AM1, AM1D, PM3, PM6 and RM1 determining the best method. the parameters to describe the reaction. The results show that the reaction for deprotonation of Lysine 9 showed better values in the Amber18 program, being close to expected through a direct transfer of Lysine 9 to Tyrosine 1154 with the RM1 method and energy barrier of 27.15 kJ/mol. The transfer of the methyl group from the SAM molecule to Lysine 9 showed that the PM6 method using the Dynamo PMF technique had an energy barrier of 72.80 kJ/mol which is close to that obtained by the experimental data.