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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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)
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)
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)
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 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)
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)
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.

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