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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Avaliação do efeito do OTSSP167 em linhagens de adenocarcinoma gástrico com amplificação do gene MELK
(Universidade Federal do Pará, 2019-12-09) PINHEIRO, Thayanne Macedo; CALCAGNO, Danielle Queiroz; http://lattes.cnpq.br/1326603355062154; https://orcid.org/0000-0002-4429-2573
Gastric cancer is considered the fifth most common type of tumor in the world, and due to its heterogeneity, it is necessary to use individualized therapies that present less toxicity and greater efficacy during treatment. In a previous study, our group reported an increased copy number of the MELK gene in approximately 55.9% of tumors in patients with gastric adenocarcinoma and such tumor cell lines. This gene encodes maternal embryonic leucine zipper kinase (MELK) protein, a member of the serine/threonine kinase family, which participates in multiple cellular processes including cell cycle progression, cell proliferation, apoptosis, cell migration, and others. The increased expression has been observed in different cancers, including gastric cancer. Thus, the present study evaluated by in silico analysis the pharmacokinetic and pharmacodynamic properties of OTSSP167, its antineoplastic activity in gastric cancer cell lines ACP03 and AGP01, analyzing cell viability, the interference of this inhibitor in the protein expression of MELK in lineages, the ability of cell invasion and migration. In silico analyses, OTSSP167 showed a high probability of intestinal absorption, grade III toxicity and higher activity score for kinase inhibition. In vitro experiments, OTSSP167 showed cytotoxic activity in gastric strains, with higher cytotoxic activity against ACP03 (IC50 = 8.5nM). Also, this inhibitor was able to reduce MELK expression in ACP03 and AGP01 strains gradually according to the concentration of the compound. Regarding migration capacity, OTSSP167 was able to significantly inhibit the migration of ACP03 cells treated for 12 hours with three different concentrations of compound (4.25nM, 8.5nM, and 17nM), but in the 24-hour analyzes, there was only significance. OTSSP167 8.5nM and 17nM concentrations. However, the evaluation of cell invasion capacity after treatment with OTSSP167 for 48 hours did not yield significant statistical results. Thus, the results suggest that OTSSP167 has antineoplastic activity in lines with MELK gene amplification and inhibits cell migration capacity. Therefore, OTSSP167 has potential applicability in future therapies, requiring additional tests to delimit the mechanism of action of the compound.
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)
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)
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)
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)
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 relacionados ao piroxicam
(Universidade Federal do Pará, 2019-12-09) OTA, Sirlene Sayuri Barros; BORGES, Rosivaldo dos Santos; http://lattes.cnpq.br/4783661132100859; https://orcid.org/0000-0003-4072-7573
Piroxicam is a drug belonging to the group of oxicams, derived from phenolic acids, in the class of NSAIDs. Although not the drug of choice in some treatments, the drug is indicated for the treatment of acute musculoskeletal disorders, post-traumatic and postoperative pain, rheumatoid arthritis and osteoarthritis, primary dysmenorrhea, endometriosis and hemorrhagic cyst. Like non-steroidal anti-inflammatory drugs, piroxicam is able to inhibit prostaglandin synthesis from arachidonic acid by competitively reversible inhibition of COX activity, with some predominance to inhibit COX-2 activity. Photosensitivity is one of the adverse effects caused by the drug, being observed in about 1% of patients. In addition, various techniques have been used to improve the stability of piroxicam without diminishing its potential. Thus, the objective of this paper is to plan, synthesize and evaluate more stable derivatives related to the phototoxicity of the study drug. Calculations of electronic properties such as high energy occupied molecular orbital (HOMO), low energy occupied molecular orbital (LUMO) and ionization potential (IP), as well as reactivity index calculations (Mulliken, CHELPG and Fukui) were calculated. performed using the Gaussview and Gaussian 2009 packages. The proposed derivatives have been synthesized through classical reactions such as esterification and nucleophilic substitution and are in the process of purification. The results of the HOMO and LUMO values showed that the D4 molecule has a better electronic distribution, with the second lowest HOMO value and the highest LUMO value, and can be considered the most stable. The D6 molecule proved to be the most reactive derivative and this can be explained by the presence of two hydroxyls in the naphthalene ring of the derivative, influencing the reactivity of the molecule. Based on the GAP values, the nitrated derivative (D2) presented lower value (3.36 eV), indicating high reactivity. The D4 molecule presented the highest GAP value, confirming its stability. In the analysis of Mulliken, CHELPG and Fukui loads of piroxicam, differences in substitution orientation were observed, probably due to the difference in calculations performed for each index. In the theoretical results of the chemical reactivity study using UV-Vis, piroxicam and its naphthalenic derivative showed completely different profiles, referring to its three main peaks, being the most expressive in the C = C system, indicating that in the benzothiazine system it functions as a reactive alkene after energy absorption.Thus, the molecular modification by the naphthalene system presented a compound with higher chemical stability and lower reactivity.
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)
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)
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.

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