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The total impact of the worldwide COVID-19 pandemic is still emerging, changing all relationships as a result, including those with pet animals. In the infection process, the use of Angiotensin-converting enzyme 2 (ACE2) as a cellular receptor to the spike protein of the new coronavirus is a fundamental step. In this sense, understanding which residue plays what role in the interaction between SARS-CoV-2 spike glycoprotein and ACE2 from cats, dogs, and ferrets is an important guide for helping to choose which animal model can be used to study the pathology of COVID-19 and if there are differences between these interactions and those occurring in the human system. Hence, trying to help to answer these questions, we performed classical molecular dynamics simulations to evaluate, from an atomistic point of view, the interactions in these systems. Our results show that there are significant differences in the interacting residues between the systems from different animal species, and the role of ACE2 key residues are different in each system and can assist in the search for different inhibitors for each animal.

The computation of accurate electron affinity (EA) remains one of the most difficult tasks in quantum chemistry. A major source of error in EA calculations is the inadequacy of the basis set (BS) to represent the anionic system, since the Gaussian exponents are normally optimized for the neutral atom energy. To overcome this problem, one must augment the BSs with diffuse functions, which allow a better description of long-range interactions in anionic systems. Here, we report a new methodology to generate BSs for accurate EA computation that consists in the direct optimization of the Gaussian exponents in an anionic environment. By using the anionic basis sets (ABSs), we substantially reduce the errors in EA calculation for boron, carbon, oxygen and fluorine. A graphical analysis of the ABS parameters shows that their exponents are able to span important regions for short- and long-ranged interactions, which permit the ABSs to properly describe both neutral and anionic systems.

Streptococcus pneumoniae is a pathogen that resides in the upper respiratory tract of healthy individuals, maintaining a commensal relationship with its host. However, the virulent form may be the etiology of pneumonia, meningitis, bacteremia, and other respiratory tract infections. Streptococcal diseases are preventable by vaccination; but currently available vaccines have some drawbacks, especially due to the high capsule variability of streptococci strains. Thus, an effective prevention strategy continues to be the focus of extensive research. In our work, several bioinformatics tools were used to identify immunogenic peptides from a selected pool of 46 conserved proteins from Streptococcus pneumoniae. In silico analysis showed that 10 proteins had epitopes with affinity for B and T lymphocytes, which were present in at least 26 different pathogens serotypes and were considered promiscuous. The multi-epitope protein, designated HC44, was designed based on these epitopes and specific linkers to improve stability and exposure to T lymphocytes. The recombinant HC44 protein was expressed in E.coli and Swiss-Webster mice were immunised by intraperitoneal injection. Immunisation with the multi-epitope HC44 protein resulted in the production of very high levels of IgG with title superior to 1/1.200.000. However, subtype IgG was highly unbalanced toward IgG1 and no protection was afforded after challenge with S.pneumoniae in a sepsis model. Thus, our strategy has been effective in constructing a highly antigenic protein but novel immunisation strategies should be investigated to reorient the immune system toward a protective response.

In prokaryotic cells, the UvrB protein plays a central role in nucleotide excision repair, which is involved in the recognition of bulky DNA lesions generated by chemical or physical agents. The present investigation aimed to characterize the uvrB gene of Corynebacterium pseudotuberculosis (CpuvrB) and evaluate its involvement in the DNA repair system of this pathogenic organism. In computational analysis, the alignment of the UvrB protein sequences of Escherichia coli, Mycobacterium tuberculosis, Bacillus caldotenax and Corynebacterium pseudotuberculosis showed high similarity and the catalytic amino acid residues and functional domains are preserved. A CpUvrB model was constructed by comparative modeling and presented structural similarity with the UvrB of E. coli. Moreover, in molecular docking analysis CpUvrB showed favorable interaction with EcUvrA and revealed a preserved ATP incorporation site. Heterologous functional complementation assays using E. coli uvrB-deficient cells exposed to UV irradiation showed that the CpUvrB protein contributed to an increased survival rate in relation to those in the absence of CpUvrB. Damaged oligonucleotides containing thymine dimer or 8-oxoguanine lesion were synthesized and incubated with CpUvrB protein, which was able to recognize and excise UV irradiation damage but not 8-oxoguanine. These results suggest that CpUvrB is involved in repairing lesions derived from UV light and encodes a protein orthologous to EcUvrB.

Malaria is responsible for more deaths around the world than any other parasitic disease. Due to the emergence of strains that are resistant to the current chemotherapeutic antimalarial arsenal, the search for new antimalarial drugs remains urgent though hampered by a lack of knowledge regarding the molecular mechanisms of artemisinin resistance. Semisynthetic compounds derived from diterpenes from the medicinal plant Wedelia paludosa were tested in silico against the Plasmodium falciparum Ca2+-ATPase, PfATP6. This protein was constructed by comparative modelling using the three-dimensional structure of a homologous protein, 1IWO, as a scaffold. Compound 21 showed the best docking scores, indicating a better interaction with PfATP6 than that of thapsigargin, the natural inhibitor. Inhibition of PfATP6 by diterpene compounds could promote a change in calcium homeostasis, leading to parasite death. These data suggest PfATP6 as a potential target for the antimalarial ent-kaurane diterpenes.

Dengue virus (DENV) has been characterized as having great clinical importance in the world, as there is no specific treatment against this virus. The NS2B-NS3pro complex is essential for the replication and maturation of DENV and is a potential pharmacological target. The present study aims to evaluate and understand the interactions and affinities (via molecular docking/AutoDock Vina) of 16 peptidomimetic derivatives applied to a NS2B-NS3pro DENV-2 complex constructed by homology modeling (via SWISS-MODEL). Two compounds were selected as potential inhibitors of this protein complex. In addition, these compounds possess important interactions involving Ser135, Gly169 and Tyr161, which have been described previously to be fundamental to the recognition of inhibitors directed to this receptor. Thus, the involvement of these residues is significant pharmacologically because they may contribute to the inhibitory action of this molecular target against DENV.

Herein, we report the antimalarial activity of nine 4-methoxychalcone derivatives 1a–i and an initial analysis of their ADMET properties. All compounds showed potent activity against the P. falciparum chloroquine-resistant clone W2, with IC50 values ranging from 1.96 µM to 10.99 µM, with moderate or low cytotoxicity against the HeLa cell line. The compound 1a (IC50 = 2.06 µM) had the best selectivity index (9.0). All the sulfonamide 4-metychalcone derivatives synthesized had cLogP values between 2 and 5 (mean value 3.79) and molecular weights (MWs) below 500. The substitution of the pyrrolidine group in 1i by a morpholine group in 1a reduced the cLogP value from 3.05 in compound 1i to 2.34 in compound 1a. Indeed, compound 1a had the highest LipE value. The binding free energy of compound 1a showed it to be the most optimal chalcone derivative for plasmepsin-2 (−7.3 Kcal/mol). The physicochemical properties and LipE analysis of the dataset allowed us to establish that compound 1a is the highest quality compound of the series and a potential oral lead candidate.

macrocycles was evaluated by the differencebetween the respective binding energies. The first-row metal binding energy is higher to polyethermacrocycle than to polyamine one. In the case of second-row transition metals, the polyamine lig-and has a higher binding energy than the polyether macrocycle. This behavior is in good agreementwith the macrocyclic cavity dimension, which has a direct relation to the ring size and metal ionsize. While the oxygen–oxygen distances are close to4Ainthepolyether macrocycle cavity, in thepolyamine one the nitrogen–nitrogen distances are close to 5 A.

In this study, the aim was to determine the complete sequence of the Copaifera langsdorffii trypsin inhibitor (CTI)-1 using 2-dimensional (2D)-PAGE, matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF), and quadrupole time-of-flight (QTOF) spectrometry. Spots A (CTI-1) and F (CTI-2) were submitted to enzymatic digestions with trypsin, SV8, and clostripain. The accurate mass of the peptide obtained from each digest was determined by mass spectrometry (MS) using MALDI-TOF. The most abundant peptides were purified and sequenced in a liquid chromatograph connected to an electrospray ionization-QTOF MS. When the purified trypsin inhibitor was submitted to 2D electrophoresis, different spots were observed, suggesting that the protein is composed of 2 subunits with microheterogeneity. Isoelectric points of 8.0, 8.5, and 9.0 were determined for the 11 kDa subunit and of 4.7, 4.6, and 4.3 for the 9 kDa subunit. The primary structure of CTI-1, determined from the mass of the peptide of the enzymatic digestions and the sequence obtained by MS, indicated 180 shared amino acid residues and a high degree of similarity with other Kunitz (KTI)-type inhibitors. The peptide also contained an Arg residue at the reactive site position. Its 3-dimensional structure revealed that this is because the structural discrepancies do not affect the canonical conformation of the reactive loop of the peptide. Results demonstrate that a detailed investigation of the structural particularities of CTI-1 could provide a better understanding of the mechanism of action of these proteins, as well as clarify its biologic function in the seeds. CTI-1 belongs to the KTI family and is composed of 2 polypeptide chains and only 1 disulfide bridge.

Malaria is the most prevalent parasitic disease in the world. Currently, an effective vaccine for malaria does not exist, and chemotherapy must be used to treat the disease. Because of increasing resistance to current antimalarial drugs, new treatments must be developed. Among the many potential molecular targets, the hexose transporter of Plasmodium falciparum (PfHT) is particularly promising because it plays a vital role in glucose transport for the parasite. Thus, this study aims to determine the three-dimensional structure of PfHT and to describe the intermolecular interactions between active glycoside derivatives and PfHT. Such information should aid in the development of new antimalarial drugs. The receptor PfHT was constructed from primary sequences deposited in the SWISS MODEL database. Next, molecular docking simulations between O-(undec-10-en)-l-D-glucose and the constructed active site models were performed using Autodock Vina. The glycoside derivative-PfHT complexes were then refined using the hybrid QM/MM (PM3/ff03) method within the AMBER package. The models were then evaluated using Ramachandran plots, which indicated that 93.2% of the residues in the refined PfHT models (P5) were present in favorable regions. Furthermore, graphical plots using ANOLEA showed that the potential energies of interaction for atoms unbonded to P5 were negative. Finally, the O-(undec-10-en)-l-D-glucose-PfHT complex was evaluated using 20-ns Molecular Dynamics simulations with an ff03 force field. Docking and QM/MM studies revealed the amino acids essential for molecular recognition of and activity on glycosides. Inhibition of glucose transporters may prevent the development and metabolism of P. falciparum, so a description of the receptor’s structure is a critical step towards rational drug design.

Cardiotonic steroids (CS), natural compounds with traditional use in cardiology, have been recently suggested to exert potent anticancer effects. However, the repertoire of molecules with Na,K-ATPase activity and anticancer properties is limited. This paper describes the synthesis of 6 new digoxin derivatives substituted (on the C17-butenolide) with γ-benzylidene group and their cytotoxic effect on human fibroblast (WI-26 VA4) and cancer (HeLa and RKO) cell lines as well as their effect on Na,K-ATPase activity and expression. As digoxin, compound BD-4 was almost 100-fold more potent than the other derivatives for cytotoxicity with the three types of cells used and was also the only one able to fully inhibit the Na,K-ATPase of HeLa cells after 24h treatment. No change in the Na,K-ATPase α1 isoform protein expression was detected. On the other hand it was 30-40 fold less potent for direct Na,K-ATPase inhibition, when compared to the most potent derivatives, BD-1 and BD-3, and digoxin. The data presented here demonstrated that the anticancer effect of digoxin derivatives substituted with γ-benzylidene were not related with their inhibition of Na,K-ATPase activity or alteration of its expression, suggesting that this classical molecular mechanism of CS is not involved in the cytotoxic effect of our derivatives.

Accurate Gaussian basis sets for atoms from H to Ba were obtained by means of the generator coordinate Hartree-Fock (GCHF) method based on a polynomial expansion to discretize the Griffin-Wheeler-Hartree-Fock equations (GWHF). The discretization of the GWHF equations in this procedure is based on a mesh of points not equally distributed in contrast with the original GCHF method. The results of atomic Hartree-Fock energies demonstrate the capability of these polynomial expansions in designing compact and accurate basis sets to be used in molecular calculations and the maximum error found when compared to numerical values is only 0.788 mHartree for indium. Some test calculations with the B3LYP exchange-correlation functional for N2, F2, CO, NO, HF, and HCN show that total energies within 1.0 to 2.4 mHartree compared to the cc-pV5Z basis sets are attained with our contracted bases with a much smaller number of polarization functions (2p1d and 2d1f for hydrogen and heavier atoms, respectively). Other molecular calculations performed here are also in very good accordance with experimental and cc-pV5Z results. The most important point to be mentioned here is that our generator coordinate basis sets required only a tiny fraction of the computational time when compared to B3LYP/cc-pV5Z calculations.

Fitases (EC 3.1.3.8), quando presentes em racoes para animais, aumentam a qualidade nutricional por aumentar a biodisponibilidade de fosfatos. Entretanto, seu uso e restrito, pois sofrem rapida degradacao pelo suco gastrico. Com objetivo de desenvolver fitase acido resistente, um modelo da fitase de Yersinia foi construido por modelagem comparativa. Inicialmente, uma busca por estruturas moldes seguida da construcao do modelo foi realizada pelo programa SWISS MODEL. O modelo construido foi avaliado quanto a estereoquimica da cadeia principal pelo PROCHECK. Finalmente, o modelo foi refinado simulacao de dinâmica molecular por 8 nanosegundos atraves do programa AMBER. Como resultado, o modelo possui as mesmas caracteristicas da estrutura molde, fitase de Escherichia coli, PDB: 1DKQ. Alem disso, o modelo resultante mostra que o residuo de histidina e capaz de interagir com o grupamento fosfato presente no fitato. Este modelo permitira realizar estudos de mutagenese dirigida in silico, capaz de desenvolver fitases com propriedades fisico-quimicas mais adequadas.

Schistosomiasis is a serious public health problem in Brazil and worldwide. Although the drugs used to treatment schistosomiasis are effective, the disease continues to expand in all endemic countries due to constant reinfection, poor sanitation, and the lack of effective programs for disease control. However, advances generated through genome projects have provided important information that has improved the understanding of the biology of this parasite. These advances, associated with the advent of bioinformatic analysis, are becoming an important tool in reverse vaccinology. Through database access to the DNA and protein sequences of Schistosoma mansoni and the use of bioinformatics programs, fourteen epitopes were identified. Five epitopes were obtained from proteins whose immunogenic potential had already been assessed in other studies (KP), and nine whose immunogenic potential is unknown (UP). To improve stimulation of the host immune system, the selected epitopes were modeled with a sugar moiety. After this addition, all of the epitopes showed structures similar to those observed in the native proteins, but only eleven of the peptides presented thermodynamically stable structures. Prediction analysis and molecular modeling showed that the glycopeptides presented here are important targets in the search for a vaccine against schistosomiasis. Additionally, they suggest that these molecules may be used in immunological assays to evaluate the level of protection, the effect on pathology reduction and the profile of cytokines and antibodies induced by them.

A detailed theoretical study of the 1,7,1l,17-tetraoxa-2,6,12,16-tetraaza-cycloeicosane ligand ([20]AneN4O4) coordinated to Fe2+, Co2+, Ni2+, Ru2+, Rh2+, and Pd2+ transition metal ions was carried out with the B3LYP method. Two different cases were performed: when nitrogen is the donor atom (1aq) and also with the oxygen as the donor atom (1bq). For all the cases performed in this study 1aq structures were always more stable than the 1bq ones. Considering each row is possible to see that the energy increases with the increase of the atomic number. The M2+ cation binding energies for the 1aq complexes increase with the following order: Fe2+ < Ru2+ < Co2+ < Ni2+ < Rh2+ < Pd2+.

A Triagem Virtual Inversa, ou Triagem Inversa, consiste em uma busca em banco de dados de estruturas proteicas, sendo estas de relevância farmacologica, de maneira a evidenciar in silico, os receptores farmacologicos de atuacao para um determinado ligante de interesse. A plataforma utilizada denomina-se sc-PDB, o qual e um software on-line que abriga somente alvos farmacologicos, sendo selecionadas a partir do PDB. O principal objetivo deste estudo e realizar o processo de TVI para neurotransmissores cujos receptores encontram-se descritos no PDB. Este estudo preliminar busca validar o metodo de TVI para uma posterior aplicacao em compostos naturais. A estrutura dos neurotransmissores da adrenalina, serotonina e adenosina foram submetidos ao programa on-line sc-PDB. Onze variaveis foram estudadas, cada uma separadamente, mantendo as demais segundo o default do programa. Apos esse procedimento foi estabelecido um protocolo, o qual sera utilizado na busca de receptores de compostos naturais. Nesse protocolo ficou estabelecido o procedimento que encontra maior numero de ligantes, na qual a molecula deve ser gerada sem os seus hidrogenios, sem estereoquimica, definindo como parâmetro de entrada subestrutura, e sem considerar variaveis como numero de ligacoes rotaveis, de aneis ou de grupos doadores e receptores de ligacao hidrogenio. 10.5216/ref.v8i1.10561

Dopamine (DA) is an important neurotransmitter in the Central Nervous System (CNS) of mammals being found in significant quantities in the brain. In a low concentration is associated with Parkinson's disease [1], which makes it important detection. However, a major problem in determining DA is its joint resolution with coexisting species such as ascorbic acid (AA). In traditional solid electrodes, AA is oxidized at a potential close to that of DA, resulting in an overlapping voltammetric response [2]. Therefore, improving the selectivity of the monitoring techniques of AD has been the focus of much research. [3] Thus, ionic liquids at ambient temperatures (RTILs) tetrafluoroborate and 1-butyl-3-methylimidazolium (BMI.BF4) can be used as electrolytes for different electrochemical reactions, which have important properties, the selectivity of them, making the technique voltammetric more efficient. Our focus as this work is to analyze the behavior of these molecules (DA and AA) amid BMI.BF4 compared to conventional solvents, using a method known as Molecular Dynamics (MD), being a powerful tool for obtaining properties structural and thermodynamic properties of these substances. MD simulations were carried out for systems in DA [BMI.BF4] and AA [BMI.BF4]. For comparison, simulations were also carried out in water. All simulations were performed using the AMBER 9 package. We also used PTRAJ to perform analyses on the data we collected, such as calculating density, total energy, RDFs and self-diffusion coefficients, and we used xmgrace and gnuplot to aid us in visualizing the data. As part of evaluating the interference between molecules (AA and DA), we show the results of analyzes of AA. In this case the average density is 1.0768 cc / mol, while the water density is 1.027 cc / mole. As the total energy of the two systems have different values and constants (-19.5 kcal / mol in the midst of water and -12.5 kcal / mol among LI) along the dynamics. This difference in energy is given by unfavorable interactions that AA has with the molecules of the LI. For a better understanding of the systems were calculated the radial distribution functions for each of statepoints. The results presented in both solvent were similar, demonstrating that the AA is added in both LI well as for water, ie they have good solvation. Regarding the results of diffusivity, the 298K and 1 atm the coefficient of self-diffusion (MSD) showed lower values compared to the water in the same conditions. This result reveals the MSD in a higher viscosity of the LI and so may be an important property for separation of molecules (AA and DA) and therefore important in electrochemical process.

A malaria e uma doenca de importância mundial. A necessidade pela busca de novas alternativas terapeuticas e reforcada devido a crescente resistencia adquirida pelo parasito aos farmacos atuais. O transportador de hexoses de Plasmodium falciparum (PfHT) tem apresentado suporte genetico para que PfHT seja utilizado como alvo para o desenvolvimento de antimalaricos, podendo com isso inibir a absorcao de glicose e eliminar os parasitas. Com o objetivo de avaliar a conformacao farmacoforica do ligante previamente ancorado ao receptor antes e apos a simulacao de dinâmica (DM) molecular. Desta forma foi possivel analisar que o processo de dinâmica molecular permitiu ao modelo estabilidade bem como caracteristicas de viabilidade mais proximas a sua utilizacao biologica. O que demonstra a impotância de ferramentas de bioinformatica em estudos de moleculas bioativas com possivel potencial farmacologico.

A malaria e uma doenca para a qual e necessario o desenvolvimento de novos antimalaricos com maior eficacia devido a crescente resistencia que o parasito vem adquirindo. O objetivo deste trabalho foi realizar uma triagem in silico a fim de encontrar compostos com maior afinidade com o receptor transportador de hexose do Plasmodium falciparum (PfHT), considerado um novo alvo molecular contra a malaria. Assim, estudos de ancoragem molecular foram realizados utilizando o software AutoDock Vina a fim de avaliar as energias de ligacao e as interacoes receptor-ligante. Os resultados mostraram que os compostos analisados podem ser potenciais antimalaricos, no entanto os compostos 28951446 e 59797532 sao os que possuem melhores energias de ligacao e interacoes entre ligante-receptor, c onstituindo assim, potenciais farmacos antimalaricos.

Devido a grande resistencia do Plasmodium falciparum as terapias ja existentes, e necessario desenvolver antimalaricos mais eficazes. Estudos anteriores tem mostrado que o receptor transportador de hexose do Plasmodium falciparum (PfHT) tem grande relevância para novos estudos, pois, a sua inibicao diminui a absorcao da glicose e, consequentemente, elimina o parasito. Nosso estudo teve como objetivos construir um modelo do receptor da PfHT capaz de descrever a atividade biologica e a conformacao farmacoforica de derivados de glicose atraves de estudos de acoplamento molecular entre ligante-receptor.

A malaria e um dos principais problemas de saude publica no mundo. A crescente resistencia adquirida pelo parasito aos farmacos atuais endossa a necessidade pela busca de novos antimalaricos. A PfHT tem se mostrado como importante alvo molecular no desenvolvimento de novos antimalaricos, por inibir a absorcao de glicose levando a morte do parasito. Com o objetivo de estudar as interacoes de receptores com a PfHT, visando o planejamento de novas moleculas bioativas que bloqueiam a biossintese e induzam a morte o parasita foram realizados estudos de dinâmica molecular das interacoes proteina-ligante da PfHT. Os resultados preliminares motivam a utilizacao do modelo do receptor da PfHT como inibidor no transporte de hexose no ciclo de vida do parasita por apresentarem estabilidade durante a interacao. Assim, novos compostos prototipos poderao ser planejados, os quais poderao ser capazes de se ligarem a este receptor de forma mais efetiva e seletiva.

A esquistossomose humana e uma doenca cronica e debilitante causada por helmintos com maior taxa de mortalidade no mundo. Neste estudo foram selecionados epitopos de proteinas da superficie do Schistosoma mansoni para construcao de uma proteina quimerica com capacidade de induzir uma resposta imune e reducao da patologia. Analises in silico foram feitas para obtencao da sequencia proteica, avaliacao de parâmetros fisicos e quimicos, e modelagem da estrutura 3D. Atraves da modelagem comparativa foram construidos modelos 3D da quimera. As analises foram refinadas por calculos moleculares seguidas de simulacao da dinâmica molecular. Os modelos refinados das estrutura das quimeras forneceu informacoes sobre a sua dobragem e a estabilidade termodinâmica. Considerando que e um modelo termodinamicamente estavel, foi realizada a sintese e expressao da quimera em linhagem de bacterias E. coli DE3-Rosetta para futuros ensaios de purificacao e analise de imunogenicidade.

A dengue e a Arbovirose mais prevalente do mundo. O virus infecta anualmente cerca de 50 a 100 milhoes depessoas, das quais 500 000 evoluem para quadros mais graves como a dengue hemorragica e a sindrome do choque da dengue, cujo indice de mortalidade atinge os 20% em alguns casos. Nao existe vacina licenciado ou terapia antiviral especifica. Na tentativa de se desenvolver estrategias terapeuticas a NS5 metiltransferase converge em um potencial alvo farmacologico para o desenvolvimento racional de farmacos,uma vez ser ela essencial para os processos de replicacao do virus na celula hospedeira. A triagem virtual de compostos em banco de dados fornece uma ferramenta importante para a obtencao de estruturas quimicas com potencial atividade farmacologica, e acoplada a analises em modelagem molecular, pode-se predizer a atividade destes compostos, reduzindo assim os gastos com a sintese e testes biologicos de moleculas candidatas a farmacos.

O virus da dengue (DENV) caracteriza-se como virus de grande importância clinica, uma vez que acometem milhoes de pessoas anualmente em todo o mundo. Estrategias para o desenvolvimento de medicamentos voltados para o combate e controle do DENV tornam-se de extrema relevância e necessidade, uma vez que ate o momento nao se tem disponivel nenhum tratamento especifico contra o mesmo. Nesse contexto, destaca-se o complexo NS2B-NS3pro, essencial para replicacao e maturacao do DENV, sendo um potencial alvo farmacologico. O presente estudo tem como objetivo avaliar os resultados de ancoragem molecular, realizada na presenca e ausencia de moleculas de agua, desenvolvido para avaliar a afinidade potenciais candidatos a inibidores de NS2B-NS3pro.

Os bancos de dados sao uma ferramenta importante de gerenciamento de informacoes. A organizacao de alvos moleculares em um banco especifico possibilita a rapida triagem de compostos prototipos e agiliza os ensaios biologicos, diminuindo os custos e o tempo de pesquisa de novos compostos bioativos. A criacao do banco de alvos moleculares ira contribuir para a maior integracao e eficiencia da pesquisa de novos farmacos na UFSJ/CCO.

DOI 10.5433/2316-5200.2013v2n4p59 Malaria e a doenca parasitaria que mais acomete o homem. Segundo a Organizacao Mundial de Saude (OMS), o aparecimento de cepas de Plasmodium resistentes a artemisinina tornam a busca de novos alvos e compostos com acao antimalarica extremamente necessaria. Neste estudo relatamos aspectos historicos, ciclo biologico, atuais farmacos, alvos moleculares passiveis de intervencao terapeutica e recentes receptores farmacologicos. Esta revisao conclui com uma breve discussao das perspectivas e dificuldades contribuindo para o avanco no desenvolvimento de novos antimalaricos.

Background The witches’ broom disease is a plague caused by Moniliophthora perniciosa in the Theobroma cacao, which has been reducing the cocoa production since 1989. This issue motivated a genome project that has showing several new molecular targets, which can be developed inhibitors in order to control the plague. Among the molecular targets obtained, the UDP-N-acetylglucosamine pyrophosphorylase (UNAcP) is a key enzyme to construct the fungal cell wall. The inhibition of this enzyme results in the fungal cell death. Results The results show that the molecular recognition of the enzyme with the substrates occurs mainly by hydrogen bonds between ligands and Arg116, Arg383, Gly381, and Lys408 amino acids; and few hydrophobic interactions with Tyr382 and Lys123 residues. Conclusions Among the compounds analyzed, the NAG5 showed the best binding energy (−95.2 kcal/mol). The next steps for the control of witches’ broom plague involve the synthesis and biological evaluation of these compounds, which are in progress.

Rabies is a zoonotic disease that mainly affects poor population in developing countries. While there is an efficient vaccine for it, many of those in the areas most affected by the disease can be unaware of the vaccine and their need for it, may be unable to reach an area where the vaccines are readily available, or may be unable to pay for the high cost of vaccination and immunoglobulin. This project aimed to find a potential treatment for the disease when it has already reached its later stages, so those who cant access vaccination still have a chance of surviving this lethal disease. This project focused on the bioinformatics capability of finding potential ligands that could inactivate or block all five proteins or rabies, so that they would be unable to bind to host receptors, or to damage the immune system of patients. All five proteins of rabies from nineteen different strains (ninety-five proteins) were modeled through homology modeling, and twenty-six drug-like ligands that passed Lipinskis rule of five were chosen. The first docking step was to put all ninety-five proteins through a blind docking with each of the twenty-six ligands to narrow down the number of ligands and analyze potential active sites. After all the blind dockings were concluded, seventeen ligands were chosen for the active site docking, which also considered specific residues (found from literature, bioinformatic tools, and analysis of blind docking) as potential active sites of each protein. The blind docking results were also visualized and analyzed for both the binding energies of each binding as well as the location of the connections. The number of times each of the residues from the potential active sites were accessed were also analyzed. The ligands that had the best results overall were narrowed down to four and analyzed both for their structure and pharmacology in the context of rabies infection. Potential active sites were also analyzed and narrowed down to the most likely active sites for each protein. A raiva é uma doença zoonótica que afeta principalmente a população pobre de países em desenvolvimento. Embora exista uma vacina eficiente contra o vírus, muitas das pessoas nas áreas mais afetadas pela doença podem não ter conhecimento da vacina e de sua necessidade, não conseguem chegar a uma área onde as vacinas estão prontamente disponíveis, ou não podem pagar pelo alto custo da vacinação e da imunoglobulina. Este projeto teve como objetivo encontrar um tratamento potencial para a doença quando ela já atingiu seus estágios mais avançados, de modo que aqueles que não têm acesso à vacinação ainda tenham uma chance de sobreviver à esta doença letal. Este projeto teve como foco a capacidade da bioinformática de encontrar potenciais ligantes que pudessem inativar ou bloquear todas as cinco proteínas ou raiva, de modo que fossem incapazes de se ligar aos receptores do hospedeiro, ou de danificar o sistema imunológico dos pacientes. Todas as cinco proteínas da raiva de dezenove cepas diferentes (noventa e cinco proteínas) foram modeladas por meio de modelagem de homologia, e vinte e seis ligantes que passaram pela regra de cinco de Lipinski foram escolhidos. A primeira etapa de docagem foi docar todas as 95 proteínas por meio de uma docagem cega com cada um dos 26 ligantes para reduzir o número de ligantes e analisar potenciais sítios ativos. Após a conclusão de todos as docagens cegas, foram escolhidos dezessete ligantes para a docagem ativa, que considerou resíduos específicos (encontrados na literatura, ferramentas de bioinformática e análise da docagem cega) como potenciais sítios ativos de cada proteína. Os resultados da docagem cega também foram visualizados e analisados quanto às energias de ligação, bem como a localização das conexões. O número de vezes que cada um dos resíduos dos potenciais sítios ativos foi acessado também foi analisado. Os ligantes que tiveram os melhores resultados gerais foram reduzidos a quatro e tiveram suas estruturas e farmacologia analisadas no contexto da infecção por raiva. Os sítios ativos potenciais também foram analisados e limitados aos sítios ativos mais prováveis para cada proteína.

As propriedades atômicas e moleculares foram obtidas pelos conjuntos de base gerados pelo Método da Coordenada Geradora Hartree-Fock Polinomial de qualidade 5Z para os átomos da primeira fila e 7Z para átomos da segunda fila da Tabela Periódica. Os resultados obtidos são comparados com os conjuntos de base de Pople (6-311G**) e de Dunning (cc-pVDZ, cc-pVTZ e cc-pVQZ, aug-cc-pVDZ e aug-cc-pVTZ), além dos conjuntos de base de Jorge (DZP, TZP e QZP), gerados pelo Método da Coordenada Geradora Hartree-Fock Melhorado. Dessa forma, tanto a acurácia na construção dos conjuntos de base é avaliada como a eficiência da abordagem polinomial. Propriedades de energia total, zero-point vibrational energy - ZPVE, comprimento de ligação, ângulo de ligação, momento de dipolo elétrico e polarizabilidade foram comparadas entre os conjuntos de base em nível de teoria MP2, CCSD(T) e DFT usando funcionais B2PLYP e B3LYP. Os conjuntos de bases gerados para moléculas neutras apresentaram vantagens significativas no tempo computacional para as maiores moléculas calculadas em comparação a conjuntos de base de qualidade quadruple-Zeta. Os mesmos resultados foram observados para os demais níveis de teoria sem grandes discrepâncias no cálculo de energia, compensando a variação no ganho do tempo computacional significativo gerado pelos conjuntos de base do MCG-HFp. O fator de escala gerou valores de ZPVE competitivos em relação aos conjuntos de base triple-Zeta para métodos DFT e CCSD(T) e próximos aos experimentais. Isso fez com que resultados de energia de atomização, mesmo com grandes variações entre os conjuntos de base, apresentassem resultados próximos aos experimentais, incluindo resultados obtidos em nível MP2. Para distância de ligação, os valores se aproximaram dos obtidos pelos conjuntos de base triple-Zeta. Comportamento similar aos observado pelo cálculo de ângulo de ligação em nível B2PLYP e B3LYP. Um comparativo da ação das funções de polarização entre os conjuntos do MCG-HFp para moléculas neutras e aniônicas são os resultados de momento de dipolo e polarizabilidade, que demonstram resultados próximos aos conjuntos triple-Zeta, para moléculas neutras, e apresentou discrepâncias nos resultados das aniônicas, objetivando futuros estudos e modificações em sua estrutura de polarização, apesar da grande vantagem no tempo computacional em relação aos conjuntos de base quadruple-Zeta. As moléculas neutras apresentaram-se bem competitivas em relação ao ganho no tempo computacional no cálculo das propriedades para um conjunto de base de maior qualidade em relação as comparadas, uma vez que conjuntos de base de qualidade quintuple-zeta demandam recurso computacional oneroso, impossibilitando seu cálculo. Dessa forma, o MCG-HFp é um conjunto de base promissor pelo tempo computacional e pouco recurso que exige nos cálculos de propriedades atômicos e moleculares. The atomic and molecular properties were obtained using basis sets generated by the Polynomial Hartree-Fock Generating Coordinate Method of quality 5Z for atoms in first row and 7Z for atoms in second row of the Periodic Table. The results are compared with the basis sets of Pople (6-311G **) and Dunning (cc-pVDZ, cc-pVTZ and cc-pVQZ, aug-cc-pVDZ and aug-cc-pVTZ), besides Jorge\'s basis sets (DZP, TZP and QZP). The latter were generated by the Improved Hartree-Fock Generating Coordinate Method. Thus, both the accuracy in the construction of the basis sets and the efficiency of the polynomial approach. Total energy, zero-point vibrational energy - ZPVE, bond length, bond angle, electrical dipole moment, and polarizability were all compared among the basis set from MP2, CCSD (T) and DFT using B2PLYP and B3LYP level of theory. The basis sets generated for neutral molecules showed significant advantages in computational time for the largest calculated molecules in comparison to quadruple-Zeta quality base sets. The same results were observed for the other levels of theory without major discrepancies in the energy calculation, compensating for the significant variation in the gain of computational time generated by the MCG-HFp basis sets. The scale factor generated competitive ZPVE values in relation to the triple-Zeta basis sets for DFT and CCSD (T) methods, and those were close to the experimental values. This caused atomization energy results, even with great variations among basis sets, to also show results close to the experimental values, including results obtained at the MP2 level. For bond distance, the values were near to those obtained by the triple-Zeta basis sets. This behavior was similar to that observed by calculating the connection angle at B2PLYP and B3LYP levels. A comparative of the action of the polarization functions between the MCG-HFp sets for neutral and anionic molecules are result of dipole moment and polarizability, which demonstrate values close to those from triple-Zeta sets for neutral molecules, and showed discrepancies in the results of the anionic, aiming at future studies and modifications in their polarization structures, despite the great advantage in computational time in relation to quadruple-Zeta base sets. The neutral molecules were very competitive regarding the gain in computational time in the calculation of properties for a base set of higher quality in relation to those compared, since basis sets of quintuple-zeta quality demand costly computational resources, making it impossible to calculate. Thus, the MCG-HFp is a promising basis set due to the computational time and little resource that it requires in the calculation of atomic and molecular properties.

Este trabalho apresenta um estudo aplicando a Teoria do Funcional da Densidade (DFT), utilizando o funcional B3LYP, para estudar a estrutura eletrônica de nanoclusters de platina dopados com Al, Cr e V e suas interações com oxigênio molecular. As análises das populações de Mulliken e de NBO para a interação entre O2 e Pt2, Pt-Cr e Pt-V revelaram que ocorre transferência de carga dos orbitais s e d dos metais para os orbitais p do oxigênio, resultando no preenchimento dos orbitais antiligantes da molécula de oxigênio, provocando a quebra da ligação O--O e formação de ligações hibridizadas Metal - O, com energia de dissociação da ligação O - O em 1,0 eV sobre Pt2. Sobre Pt-Cr e Pt-V, esse valor decresce para 0,56 eV e 0,20 eV, respectivamente. Os estudos da interação entre oxigênio molecular e os clusters Pt3, Pt2Al, Pt2Cr e Pt2V mostram que ocorre adsorção não dissociativa de oxigênio molecular sobre o cluster Pt3 onde observamos uma adsorção segundo o modelo de ponte enquanto que sobre os clusters Pt2Al e Pt2V ocorre adsorção dissociativa de oxigênio molecular. Por outro lado, com o cluster Pt2Cr a adsorção segue o modelo de Pauling, com o oxigênio molecular adsorvido em apenas um sítio do cluster, que foi o átomo Pt, sem a quebra da ligação O--O. Curvas de superfície de energia potencial para a dissociação de oxigênio molecular sobre Pt2Al e Pt2V mostraram um valor de aproximadamente 0,21 eV para a barreira de dissociação da ligação O--O adsorvido sobre o cluster Pt2Al e aproximadamente 0,30 eV para a barreira de dissociação da ligação O--O adsorvido sobre o cluster Pt2V. Os estudos da interação entre oxigênio molecular e os clusters Pt4, Pt3Al, Pt3Cr e Pt3V mostram que ocorre adsorção não dissociativa de oxigênio molecular sobre os clusters Pt4 e Pt3Cr onde foi observado que a adsorção segue o modelo de ponte. Por outro lado, sobre os clusters Pt3Al e Pt3V a adsorção de oxigênio molecular também seguiu o modelo ponte, com dissociação da ligação O - O. Encontramos um valor de 0,46 eV para a barreira de dissociação da ligação O--O adsorvido sobre o cluster Pt3Al e aproximadamente 0,28 eV para a barreira energética de dissociação da ligação O--O adsorvido sobre o cluster Pt3V. Os estudos para interação entre oxigênio molecular e os clusters Pt5, Pt4Al, Pt4Cr e Pt4V revelaram que ocorre adsorção dissociativa de oxigênio molecular sobre os clusters Pt4Al e Pt4V, onde observamos uma adsorção que segue o modelo de ponte enquanto que sobre o cluster Pt5 a adsorção segue o modelo de ponte sem dissociação da ligação O--O. Por outro lado, a adsorção sobre Pt4Cr segue o modelo de Pauling, com o oxigênio molecular adsorvido em apenas um sítio do cluster, sem a quebra da ligação O--O. Curvas de superfície de energia potencial mostraram um valor de aproximadamente 0,62 eV para a barreira de dissociação da ligação O--O adsorvido sobre o cluster Pt4Al e aproximadamente 0,20 eV para a barreira energética de dissociação da ligação O--O adsorvido sobre o cluster Pt4V. This work presents a study applying the Density Functional Theory (DFT) using the B3LYP functional to study the electronic structure of platinum nanoclusters doped with Al, Cr and V and their interactions with molecular oxygen. The analysis of Mulliken populations and NBO for the interaction between O2 and Pt2, Pt-Cr and Pt-V showed that charge transfer occurs orbital sed metals for the p orbitals of oxygen, resulting in the filling of the antibonding orbitals of the molecule oxygen, causing the cleavage of O-O and bond forming hybridized Metal - O, bond dissociation energy of O - O on Pt2 about 1.0 eV. On Pt-Cr and Pt-V, this value decreases to 0.56 eV and 0.20 eV, respectively. Studies of the interaction between molecular oxygen and the Pt3 clusters, Pt2Al, Pt2Cr and Pt2V show that no dissociative adsorption occurs for molecular oxygen on the cluster Pt3 where we observe a second adsorption model bridge while on clusters Pt2Al and Pt2V dissociative adsorption occurs of molecular oxygen. Moreover, with the cluster Pt2Cr adsorption follows the model of Pauling, with molecular oxygen adsorbed on only one site in the cluster, which was the Pt atom, without the cleavage of the O-O. Curves of potential energy surface for dissociation of molecular oxygen on Pt2Al and Pt2V showed a value of about 0.21 eV for the bond dissociation barrier of the O-O adsorbed on the cluster Pt2Al approximately 0.30 eV and for the barrier The bond dissociation O-O adsorbed on the cluster Pt2V. Studies of the interaction between molecular oxygen and clusters Pt4, Pt3Al, Pt3Cr and Pt3V show that no dissociative adsorption occurs for molecular oxygen on clusters Pt4 and Pt3Cr where it was observed that the adsorption follows the model of the bridge. On the other hand, on clusters Pt3Al and Pt3V adsorption of molecular oxygen also followed the model bridge, with bond dissociation O - O. We found a value of 0.46 eV for the barrier to bond dissociation to O-O adsorbed on the cluster Pt3Al and approximately 0.28 eV for bond dissociation of the O-O adsorbed on the cluster Pt3V. Studies on the interaction between molecular oxygen and clusters Pt5, Pt4Al, Pt4Cr and Pt4V revealed that occurs dissociative adsorption of molecular oxygen on clusters Pt4Al and Pt4V, where we observe an adsorption model that follows the bridge while on the adsorption cluster Pt5 follows the bridge model without the bond dissociation. Moreover, adsorption is modeled on Pt4Cr Pauling with oxygen adsorbed on only one site of the cluster, without the cleavage of the O-O. Curves of potential energy surface showed a value of about 0.62 eV for the bond dissociation barrier of the O-O adsorbed on the cluster Pt4Al and approximately 0.20 eV energy barrier for bond dissociation of the O-O adsorbed on the Pt­4V cluster.

Made available in DSpace on 2016-09-23T14:09:19Z (GMT). No. of bitstreams: 1 PIBE0056.pdf: 995962 bytes, checksum: 2b0e6d5bfd2c4c55498341a409e7692c (MD5) Previous issue date: 2009-07-31 CNPQ A remoção de enxofre (S) de combustíveis fósseis, motivada pelas novas especificações legais do teor de S (valores menores que 100 ppm) já vêm sendo implementadas desde 2006. Entretanto, o nível de exigência nacional e internacional para o arrefecimento da concentração de enxofre representa uma redução muito grande e dificilmente poderá ser atingida com a tecnologia convencional, já que para atingir tais patamares é necessário uma dessulfurização muito acentuada, ou seja, mais de 95% de conversão. Pesquisas recentes, visando uma redução de compostos sulfurados em combustíveis líquidos, principalmente em busca de geração de produtos menos agressivos à natureza e custos mais baixos que os da HDS, mostram destaque para o processo de adsorção, quer combinado ao hidrotratamento quer em substituição a este. O método da adsorção, utilizando materiais como zeólitas e carvões, baseia-se no princípio de que adsorventes específicos são capazes de seletivamente capturar compostos como tióis (mercaptanos), tiofenos e benzotiofenos, ainda presentes nas correntes efluentes dos sistemas de dessulfurização. Como as zeolitas apresentam propriedades de seletividade de forma e de adsorção, são candidatas atrativas para este processo. Testes preliminares com a zeolita ZSM-5 modificada com nióbio, mostraram uma maior interação do sólido com o tiofeno nas concentrações de 3,4% e 9,1% de Nb, sendo observado que em concentrações acima de 9,1% ocorre uma diminuição na adsorção de tiofeno, possivelmente devido à presença de uma monocamada de óxido de nióbio na superfície do suporte zeolítico. Especula-se também que nesses adsorventes a ligação de compostos tiofênicos ocorre seletivamente por complexação pi. Nesse sentido, o presente trabalho propõe investigar as propriedades de adsorventes zeolíticos modificados com nióbio em processos de dessulfurização, mediante a adsorção de tiofeno, esperando que, além da adsorção sobre a zeólita (pelas hidroxilas), ocorra uma interação do tiofeno com as espécies ativas de nióbia formadas na superfície do suporte zeolítico. No presente estudo, o tiofeno será utilizado como molécula modelo representativa dos compostos sulfurados em combustíveis automotivos.