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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Desenvolvimento de candidatos a fármacos para tratamento da Leucemia Mielóide Crônica a partir do Imatinibe
(Universidade Federal do Pará, 2020-02-28) SANCHES, Vitor Hugo da SIlva; SANTOS, Cleydson Breno Rodrigues dos; http://lattes.cnpq.br/4851715640991871; https://orcid.org/0000-0002-0271-335X
Chronic Myeloid Leukemia (CML) is a chronic clonal myeloproliferative disease, characterized by leukocytosis with left shift, splenomegaly and the presence of the Philadelphia (Ph) chromosome, which results from the reciprocal and balanced translocation between the advanced states of chromosomes 9q34 and 22q11, generating a hybrid protein BCR-ABL, with increased activity of tyrosine kinase. Thus, it carried out a virtual screening study based on the ligand Imatinib, with a defined crystallographic pose, deposited under the code PDB ID 1IEP. Six databases of merchants were used to select molecules, using the software ROCS (shape similarity) and EON (electrostatic similarity), followed by pharmacokinetic and toxicological predictions in silicon, resulting in 9 methods with satisfactory values, compared with Imatinib , which were submitted to a study of biological activity prediction via PASS Prediction online server, resulting in two structures with Probability of being "active" (Pa) values for protein kinase inhibition activity, such as LMQC01 molecules (Pa = 0.457) and LMQC04 (Pa = 0.658), selected for the study of molecular docking. Use a Pyrx 0.8 graphical interface, to evaluate as likely interactions with amino acid residues and binding affinity as structures with the BCR-ABL active site, resulting in -8.6Kcal / mol-1 for structure LMQC01 and -12.2Kcal / mol -1 for LMQC04, with the LMQC04 structure reaching a value higher than the experimental binding affinity of imatinib (-11.18Kcal / mol-1), being the one selected as a drug promoter for further studies.
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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.
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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.
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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.
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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)
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.
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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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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.
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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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