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BACKGROUND: The molecular dynamics is an approach to obtain kinetic and thermodynamic characteristics of biomolecular structures. The molecular dynamics simulation softwares are very useful, however, most of them are used in command line form and continue with the same common implementation difficulties that plague researchers who are not computer specialists. RESULTS: Here, we have developed the VisualDynamics-a WEB tool developed to automate biological simulations performed in Gromacs using a graphical interface to make molecular dynamics simulation user-friendly task. In this new application the researcher can submit a simulation of the protein in the free form or complexed with a ligand. Can also download the graphics analysis and log files at the end of the simulation. CONCLUSIONS: VisualDynamics is a tool that will accelerate implementations and learning in the area of molecular dynamics simulation. Freely available at https://visualdynamics.fiocruz.br/login , is supported by all major web browsers. VisualDynamics was developed with Flask, which is a Python-based free and open-source framework for web development. The code is freely available for download at GitHub https://github.com/LABIOQUIM/visualdynamics .
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Simulação de Dinâmica Molecular , Software , Proteínas/química , Cinética , NavegadorRESUMO
Resumen El artículo se encarga de mostrar que los trabajos experimentales que tienen por objeto examinar principios de justicia distributiva en niños pueden ser leídos desde su relación con la variable demográfica género. Al efectuar esta lectura crítica desde una revisión temática se hace posible observar que los estudios, en términos generales, muestran hallazgos en tres direcciones: inexistencia de diferencias de género; diferencias no significativas y diferencias significativas. Estos resultados, sin embargo, se hallan directamente relacionados tanto con las edades de los participantes como con especificidades metodológicas de la experimentación. Con el objeto de dar cuenta de estos aspectos, el texto se ha dividido en tres partes: estudios de primera persona, trabajos de tercera persona y comparaciones culturales.
Abstract The article shows that experimental studies that aim to examine principles of distributive justice in children can be read from their relationship with the demographic variable gender. By making this critical reading from a thematic review, it is possible to observe that the studies, in general terms, show findings in three directions: no gender differences; non-significant differences; and significant differences. These results, however, are directly related both to participants' age and methodological specificities of the experimentation. In order to account for these aspects, the text is divided into three parts: first-person studies, third-person work, and cultural comparisons.
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The present work introduces a systematic decision making process which, based on Stochastic Multicriteria Acceptability Analysis - Matching, is aimed at supporting the selection of pedagogical strategies according to the theoretical paradigms provided by the Color Theory and the Learning Styles concept. This novel procedure is illustrated by an example which allowed comparison with the traditional decision mechanism. The results show that the innovation is valuable for case, since it allows a more tuned-to-reality solution that prioritizes relevant pedagogical strategies and discards insignificant ones. Another underlying advantage of this novel process as compared to the traditional one is the possibility it offers to develop a broader and more detailed analysis, since it provides both the set of pedagogical strategies for a course or group of students and a personalized analysis for each student, thus facilitating the teacher's work.
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Due to the high rate of transmissibility, Brazil became the new COVID-19 outbreak epicenter and, since then, is being monitored to understand how SARS-CoV-2 mutates and spreads. We combined genomic and structural analysis to evaluate genomes isolated from different regions of Brazil and show that the most prevalent mutations were located in the S, N, ORF3a and ORF6 genes, which are involved in different stages of viral life cycle and its interaction with the host cells. Structural analysis brought to light the positions of these mutations on protein structures, contributing towards studies of selective structure-based drug discovery and vaccine development.
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COVID-19/genética , Mutação/genética , SARS-CoV-2/genética , Proteínas Virais/genética , Brasil , Genoma Viral , Genômica , Humanos , SARS-CoV-2/patogenicidade , Índice de Gravidade de DoençaRESUMO
In this study, we have investigated the enzyme shikimate 5-dehydrogenase from the causative agent of tuberculosis, Mycobacterium tuberculosis. We have employed a mixture of computational techniques, including molecular dynamics, hybrid quantum chemical/molecular mechanical potentials, relaxed surface scans, quantum chemical descriptors and free-energy simulations, to elucidate the enzyme's reaction pathway. Overall, we find a two-step mechanism, with a single transition state, that proceeds by an energetically uphill hydride transfer, followed by an energetically downhill proton transfer. Our mechanism and calculated free energy barrier for the reaction, 64.9 kJ mol- 1, are in good agreement with those predicted from experiment. An analysis of quantum chemical descriptors along the reaction pathway indicated a possibly important, yet currently unreported, role of the active site threonine residue, Thr65.
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Oxirredutases do Álcool/metabolismo , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/enzimologia , Teoria Quântica , Oxirredutases do Álcool/química , Biocatálise , Especificidade por SubstratoRESUMO
Prions are proteins that cause a group of invariably fatal neurodegenerative diseases, one of the most known being bovine spongiform encephalopathy. The three-dimensional structure of PrPSc , the altered isoform of the prion protein, has not been fully elucidated yet, and studies on prion conversion mechanisms must rely on hypothetical ß-rich structures. Experimental and computational studies indicate that the use of low pH is capable to produce a gain of ß-structure content in the otherwise unstructured N-terminal region. These in silico studies have used different PrP fragments from distinct organisms, and with different lengths and simulation protocols, making it difficult to identify the influence of the force fields on the formation of such structures. Here, we performed a systematic study of the influence of six well-established force fields (GROMOS96 53a6, GROMOS96 43a1, AMBER99SB, AMBER99SB-ILDN, CHARMM27, and OPLS-AA/L) on the process of structural conversion of the Syrian hamster cellular prion protein simulated at acidic and neutral pH. From our analysis, we observe a strong dependence of the results with the different force fields employed. Additionally, only GROMOS96 53A6 and AMBER99SB force fields are capable to capture a high ß-sheet formation at acidic pH and adequately reproduce the neutral pH. In both cases, the ß-sheet elongation seems to be guided by the movement of the N-terminal tail toward the N-terminal of α-helix HB under acidic condition. These results comprise the most wide-ranging study to date correlating force fields to structural changes in the cellular prion protein. © 2018 Wiley Periodicals, Inc.
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Simulação de Dinâmica Molecular , Proteínas Priônicas/química , Animais , Bovinos , Concentração de Íons de Hidrogênio , Estrutura Secundária de ProteínaRESUMO
The PI3K/Akt/mTOR pathway is an important intracellular signaling pathway in cell cycle regulation and its dysregulation is associated with various types of diseases. mTOR (mechanistic or mammalian target of rapamycin) is the main enzyme that performs intermediate control of the signaling pathway through a phosphotransfer process. The classical inhibition of the mTOR pathway is effected by rapamycin and its analogous blocking allosterically the catalytic phosphorylation site, avoiding the deleterious side effects induced by ATP-competitive inhibitors. We employed ligand-based drug design strategies such as pharmacophore searching and analysis, molecular docking, absorption, distribution, metabolism, excretion and toxicity (ADMETox) properties filtering, and molecular dynamics to select potential molecules to become non-ATP competitive inhibitors of the mTOR complex. According to our findings, we propose eight novel potential mTOR inhibitors with similar or better properties than the classic inhibitor complex, rapamycin.
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Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Serina-Treonina Quinases TOR/química , Sítios de Ligação , Desenho de Fármacos , Humanos , Ligantes , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
To speed up the drug-discovery process, molecular dynamics (MD) calculations performed in GROMACS can be coupled to docking simulations for the post-screening analyses of large compound libraries. This requires generating the topology of the ligands in different software, some basic knowledge of Linux command lines, and a certain familiarity in handling the output files. LiGRO-the python-based graphical interface introduced here-was designed to overcome these protein-ligand parameterization challenges by allowing the graphical (non command line-based) control of GROMACS (MD and analysis), ACPYPE (ligand topology builder) and PLIP (protein-binder interactions monitor)-programs that can be used together to fully perform and analyze the outputs of complex MD simulations (including energy minimization and NVT/NPT equilibration). By allowing the calculation of linear interaction energies in a simple and quick fashion, LiGRO can be used in the drug-discovery pipeline to select compounds with a better protein-binding interaction profile. The design of LiGRO allows researchers to freely download and modify the software, with the source code being available under the terms of a GPLv3 license from http://www.ufrgs.br/lasomfarmacia/ligro/ .
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Descoberta de Drogas/métodos , Ligantes , Simulação de Dinâmica Molecular , Proteínas/química , Software , Biologia Computacional/métodos , Ligação Proteica , Proteínas/metabolismo , Interface Usuário-ComputadorRESUMO
The neurohormone oxytocin is a key player in the modulation of reproductive and social behavioral traits, such as parental care. Recently, a correlation between different forms of oxytocin and behavioral phenotypes has been described in the New World Monkeys (NWMs). Here, we demonstrate that, compared with the Leu8OXT found in most placental mammals, the Cebidae Pro8OXT and Saguinus Val3Pro8OXT taxon-specific variants act as equi-efficacious agonists for the Gq-dependent pathway but are weaker agonists for the ß-arrestin engagement and subsequent endocytosis toward the oxytocin receptor (OXTR). Upon interaction with the AVPR1a, Pro8OXT and the common Leu8OXT yielded similar signaling profiles, being equally efficacious on Gq and ß-arrestin, while Val3Pro8OXT showed reduced relative efficacy toward ß-arrestin. Intranasal treatment with either of the variants increased maternal behavior and also promoted unusual paternal care in rats, as measured by pup-retrieval tests. We therefore suggest that Val3Pro8OXT and Pro8OXT are functional variants, which might have been evolutionarily co-opted as an essential part of the adaptive genetic repertoire that allowed the emergence of taxon-specific complex social behaviors, such as intense parental care in the Cebidae and the genus Saguinus.
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Comportamento Animal/efeitos dos fármacos , Comportamento Materno/efeitos dos fármacos , Ocitocina/farmacologia , Comportamento Paterno/efeitos dos fármacos , Administração Intranasal , Animais , Animais Recém-Nascidos , Feminino , Variação Genética , Células HEK293 , Humanos , Masculino , Ocitocina/administração & dosagem , Ocitocina/genética , Platirrinos , Ratos , Receptores de Ocitocina/agonistas , Receptores de Ocitocina/genética , Receptores de Ocitocina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
The mTOR (mammalian or mechanistic Target Of Rapamycin), a complex metabolic pathway that involves multiple steps and regulators, is a major human metabolic pathway responsible for cell growth control in response to multiple factors and that is dysregulated in various types of cancer. The classical inhibition of the mTOR pathway is performed by rapamycin and its analogs (rapalogs). Considering that rapamycin binds to an allosteric site and performs a crucial role in the inhibition of the mTOR complex without causing the deleterious side effects common to ATP-competitive inhibitors, we employ ligand-based drug design strategies, such as virtual screening methodology, computational determination of ADME/Tox properties of selected molecules, and molecular dynamics in order to select molecules with the potential to become non-ATP-competitive inhibitors of the mTOR enzymatic complex. Our findings suggest five novel potential mTOR inhibitors, with similar or better properties than the classic inhibitor complex, rapamycin.
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Trifosfato de Adenosina/química , Antibióticos Antineoplásicos/química , Inibidores de Proteínas Quinases/química , Sirolimo/química , Serina-Treonina Quinases TOR/química , Sítio Alostérico , Desenho de Fármacos , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Relação Estrutura-Atividade , Especificidade por Substrato , Serina-Treonina Quinases TOR/antagonistas & inibidores , Termodinâmica , Interface Usuário-ComputadorRESUMO
Anthracyclines, e.g., doxorubicin (DOX), and anthracenediones, e.g., mitoxantrone (MTX), are drugs used in the chemotherapy of several cancer types, including solid and non-solid malignancies such as breast cancer, leukemia, lymphomas, and sarcomas. Although they are effective in tumor therapy, treatment with these two drugs may lead to side effects such as arrhythmia and heart failure. At the same clinically equivalent dose, MTX causes slightly reduced cardiotoxicity compared with DOX. These drugs interact with iron to generate reactive oxygen species (ROS), target topoisomerase 2 (Top2), and impair mitochondria. These are some of the mechanisms through which these drugs induce late cardiomyopathy. In this review, we compare the cardiotoxicities of these two chemotherapeutic drugs, DOX and MTX. As described here, even though they share similarities in their modes of toxicant action, DOX and MTX seem to differ in a key aspect. DOX is a more redox-interfering drug, while MTX induces energy imbalance. In addition, DOX toxicity can be explained by underlying mechanisms that include targeting of Top2 beta, mitochondrial impairment, and increases in ROS generation. These modes of action have not yet been demonstrated for MTX, and this knowledge gap needs to be filled.
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Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Cardiopatias/induzido quimicamente , Mitoxantrona/toxicidade , Miócitos Cardíacos/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Animais , Antígenos de Neoplasias/metabolismo , Cardiotoxicidade , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/prevenção & controle , Humanos , Ferro/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Ligação a Poli-ADP-Ribose , Espécies Reativas de Oxigênio/metabolismo , Inibidores da Topoisomerase II/farmacologiaRESUMO
In the present study, we investigated whether maternal exposure to a cafeteria diet affects the metabolism and body composition of offspring and whether such an exposure has a cumulative effect during the lifetime of the offspring. Female rats were fed a control (CON) or a cafeteria (CAF) diet from their own weaning to the weaning of their offspring. At 21 d of age, male offspring were divided into four groups by diet during gestation and after weaning (CON-CON, CON-CAF, CAF-CON and CAF-CAF). Blood was collected from dams (after weaning) and pups (at 30 and 120 d of age) by decapitation. CAF dams had significantly greater body weight and adipose tissue weight and higher concentrations of total cholesterol, insulin and leptin than CON dams (Student's t test). The energy intake of CAF rats was higher than that of CON rats regardless of the maternal diet (two-way ANOVA). Litters had similar body weights at weaning and at 30 d of age, but at 120 d, CON-CAF rats were heavier. At both ages, CAF rats had greater adipose tissue weight than CON rats regardless of the maternal diet, and the concentrations of TAG and cholesterol were similar between the two groups, as were blood glucose concentrations at 30 d of age. However, at 120 d of age, CAF rats were hyperglycaemic, hyperinsulinaemic and hyperleptinaemic regardless of the maternal diet. These findings suggest that maternal obesity does not modulate the metabolism of male offspring independently, modifying body weight only when associated with the intake of a cafeteria diet by the offspring.
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Tecido Adiposo , Peso Corporal , Dieta/efeitos adversos , Leptina/sangue , Doenças Metabólicas/etiologia , Obesidade/etiologia , Fenômenos Fisiológicos da Nutrição Pré-Natal , Animais , Glicemia/metabolismo , Colesterol/sangue , Dieta/normas , Feminino , Hiperglicemia/sangue , Hiperglicemia/etiologia , Hiperinsulinismo/sangue , Hiperinsulinismo/etiologia , Insulina/sangue , Masculino , Doenças Metabólicas/sangue , Gravidez , Complicações na Gravidez/etiologia , Ratos , Ratos Wistar , Triglicerídeos/sangue , DesmameRESUMO
BACKGROUND: Tuberculosis (TB) still remains one of the most deadly infectious diseases in the world. Mycobacterium tuberculosis ß-ketoacyl-ACP Reductase (MabA) is a member of the fatty acid elongation system type II, providing precursors of mycolic acids that are essential to the bacterial cell growth and survival. MabA has been shown to be essential for M. tuberculosis survival and to play a role in intracellular signal transduction of bacilli. FINDINGS: Here we describe site-directed mutagenesis, recombinant protein expression and purification, steady-state kinetics, fluorescence spectroscopy, and molecular modeling for S140T and S140A mutant MabA enzymes. No enzyme activity could be detected for S140T and S140A. Although the S140T protein showed impaired NADPH binding, the S140A mutant could bind to NADPH. Computational predictions for NADPH binding affinity to WT, S140T and S140A MabA proteins were consistent with fluorescence spectroscopy data. CONCLUSIONS: The results suggest that the main role of the S140 side chain of MabA is in catalysis. The S140 side chain appears to also play an indirect role in NADPH binding. Interestingly, NADPH titrations curves shifted from sigmoidal for WT to hyperbolic for S140A, suggesting that the S140 residue may play a role in displacing the pre-existing equilibrium between two forms of MabA in solution. The results here reported provide a better understanding of the mode of action of MabA that should be useful to guide the rational (function-based) design of inhibitors of MabA enzyme activity which, hopefully, could be used as lead compounds with anti-TB action.
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Oxirredutases do Álcool/metabolismo , Proteínas de Bactérias/metabolismo , Mycobacterium tuberculosis/enzimologia , Serina/metabolismo , 3-Oxoacil-(Proteína Carreadora de Acil) Redutase , Oxirredutases do Álcool/química , Oxirredutases do Álcool/genética , Substituição de Aminoácidos , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Sítios de Ligação/genética , Humanos , Ligação de Hidrogênio , Cinética , Modelos Moleculares , Mutagênese Sítio-Dirigida , Mutação , Mycobacterium tuberculosis/genética , NADP/química , NADP/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Proteínas Recombinantes/metabolismo , Serina/genética , Espectrometria de Fluorescência , Tuberculose/microbiologiaRESUMO
Consumption has been a scourge of mankind since ancient times. This illness has charged a high price to human lives. Many efforts have been made to defeat Mycobacterium tuberculosis (Mt). The M. tuberculosis purine nucleoside phosphorylase (MtPNP) is considered an interesting target to pursuit new potential inhibitors, inasmuch it belongs to the purine salvage pathway and its activity might be involved in the mycobacterial latency process. Here we present the MtPNP crystallographic structure associated with acyclovir and phosphate (MtPNP:ACY:PO(4)) at 2.10 Å resolution. Molecular dynamics simulations were carried out in order to dissect MtPNP:ACY:PO(4) structural features, and the influence of the ligand in the binding pocket stability. Our results revealed that the ligand leads to active site lost of stability, in agreement with experimental results, which demonstrate a considerable inhibitory activity against MtPNP (K(i) = 150 nM). Furthermore, we observed that some residues which are important in the proper ligand's anchor into the human homologous enzyme do not present the same importance to MtPNP. Therewithal, these findings contribute to the search of new specific inhibitors for MtPNP, since peculiarities between the mycobacterial and human enzyme binding sites have been identified, making a structural-based drug design feasible.
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Aciclovir/farmacologia , Mycobacterium tuberculosis/enzimologia , Purina-Núcleosídeo Fosforilase/metabolismo , Cristalografia por Raios X , Modelos Moleculares , Simulação de Dinâmica Molecular , Análise de Componente Principal , Conformação Proteica , Purina-Núcleosídeo Fosforilase/antagonistas & inibidores , Purina-Núcleosídeo Fosforilase/química , Espectrometria de FluorescênciaRESUMO
Cytidine deaminase (CDA) is a key enzyme in the pyrimidine salvage pathway. It is involved in the hydrolytic deamination of cytidine or 2'-deoxycytidine to uridine or 2'-deoxyuridine, respectively. Here we report the crystal structures of Mycobacterium tuberculosis CDA (MtCDA) in complex with uridine (2.4 Å resolution) and deoxyuridine (1.9 Å resolution). Molecular dynamics (MD) simulation was performed to analyze the physically relevant motions involved in the protein-ligand recognition process, showing that structural flexibility of some protein regions are important to product binding. In addition, MD simulations allowed the analysis of the stability of tetrameric MtCDA structure. These findings open-up the possibility to use MtCDA as a target in future studies aiming to the rational design of new inhibitor of MtCDA-catalyzed chemical reaction with potential anti-proliferative activity on cell growth of M. tuberculosis, the major causative agent of tuberculosis.
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Citidina Desaminase/metabolismo , Desoxiuridina/metabolismo , Mycobacterium tuberculosis/enzimologia , Uridina/metabolismo , Sítios de Ligação , Cristalografia por Raios X , Citidina Desaminase/química , Simulação de Dinâmica Molecular , Mycobacterium tuberculosis/química , Ligação ProteicaRESUMO
Purine nucleoside phosphorylase (PNP) (EC.2.4.2.1) is an enzyme that catalyzes the cleavage of N-ribosidic bonds of the purine ribonucleosides and 2-deoxyribonucleosides in the presence of inorganic orthophosphate as a second substrate. This enzyme is involved in purine-salvage pathway and has been proposed as a promising target for design and development of antimalarial and antibacterial drugs. Recent elucidation of the three-dimensional structure of PNP by X-ray protein crystallography left open the possibility of structure-based virtual screening initiatives in combination with molecular dynamics simulations focused on identification of potential new antimalarial drugs. Most of the previously published molecular dynamics simulations of PNP were carried out on human PNP, a trimeric PNP. The present article describes for the first time molecular dynamics simulations of hexameric PNP from Plasmodium falciparum (PfPNP). Two systems were simulated in the present work, PfPNP in ligand free form, and in complex with immucillin and sulfate. Based on the dynamical behavior of both systems the main results related to structural stability and protein-drug interactions are discussed.
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Simulação de Dinâmica Molecular , Plasmodium falciparum/enzimologia , Multimerização Proteica , Purina-Núcleosídeo Fosforilase/química , Sítios de Ligação , Biocatálise , Estabilidade Enzimática , Fosfatos/metabolismo , Maleabilidade , Estrutura Terciária de Proteína , Nucleosídeos de Purina/química , Nucleosídeos de Purina/metabolismo , Purina-Núcleosídeo Fosforilase/metabolismo , Pirimidinonas/química , Pirimidinonas/metabolismo , Sulfatos/metabolismo , Fatores de TempoRESUMO
In humans, purine nucleoside phosphorylase (HsPNP) is responsible for degradation of deoxyguanosine, and genetic deficiency of this enzyme leads to profound T-cell mediated immunosuppression. HsPNP is a target for inhibitor development aiming at T-cell immune response modulation. Here we report the crystal structure of HsPNP in complex with 7-deazaguanine (HsPNP:7DG) at 2.75 A. Molecular dynamics simulations were employed to assess the structural features of HsPNP in both free form and in complex with 7DG. Our results show that some regions, responsible for entrance and exit of substrate, present a conformational variability, which is dissected by dynamics simulation analysis. Enzymatic assays were also carried out and revealed that 7-deazaguanine presents a lower inhibitory activity against HsPNP (K(i)=200 microM). The present structure may be employed in both structure-based design of PNP inhibitors and in development of specific empirical scoring functions.
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Guanina/análogos & derivados , Simulação de Dinâmica Molecular , Purina-Núcleosídeo Fosforilase/química , Purina-Núcleosídeo Fosforilase/metabolismo , Difração de Raios X/métodos , Guanina/química , Guanina/metabolismo , Humanos , Estrutura Molecular , Análise de Componente Principal , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Espectrometria de FluorescênciaRESUMO
Purine Nucleoside Phosphorylase (PNP) catalyzes the reversible phosphorolysis of N-glycosidic bonds of purine nucleosides and deoxynucleosides, except for adenosine, to generate ribose 1-phosphate and the purine base. PNP has been submitted to intensive structural studies. This work describes for the first time a structural model of PNP from Streptococcus pyogenes (SpPNP). We modeled the complexes of SpPNP with six different ligands in order to determine the structural basis for specificity of these ligands against SpPNP. Molecular dynamics (MD) simulations were performed in order to evaluate the overall stability of SpPNP model. The analysis of the MD simulation was assessed mainly by principal component analysis (PCA) to explore the trimeric structure behavior. Structural comparison, between SpPNP and human PNP, was able to identify the main features responsible for differences in ligand-binding affinities, such as mutation in the purine-binding site and in the second phosphate-binding site. The PCA analysis suggests a different behavior for each subunit in the trimer structure.
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Simulação por Computador , Modelos Moleculares , Purina-Núcleosídeo Fosforilase/química , Streptococcus pyogenes/enzimologia , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Ligantes , Dados de Sequência Molecular , Purina-Núcleosídeo Fosforilase/metabolismo , Alinhamento de SequênciaRESUMO
Drug development has become the Holy Grail of many structural bioinformatics groups. The explosion of information about protein structures, ligand-binding affinity, parasite genome projects, and biological activity of millions of molecules opened the possibility to correlate this scattered information in order to generate reliable computational models to predict the likelihood of being able to modulate a target with a small-molecule drug. Computational methods have shown their potential in drug discovery and development allied with in vitro and in vivo methodologies. The present review discusses the main bioinformatics tools available for drug discovery and development.