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1.
J Inherit Metab Dis ; 42(1): 128-139, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30740731

RESUMO

PURPOSE: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations. METHODS: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres. RESULTS: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns. CONCLUSIONS: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.

2.
Sci Rep ; 7(1): 16575, 2017 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-29185486

RESUMO

Cardiac arrest (CA) is not a uniform condition and its pathophysiology strongly depends on its cause. In this work we have used a metabolomics approach to study the dynamic metabolic changes occurring in the plasma samples of a swine model following two different causes of CA, namely asphyxia (ACA) and ventricular fibrillation (VFCA). Plasma samples were collected at baseline and every minute during the experimental phases. In order to identify the metabolomics profiles characterizing the two pathological entities, all samples were analysed by 1H NMR spectroscopy and LC-MS/MS spectrometry.The metabolomics fingerprints of ACA and VFCA significantly differed during the peri-arrest period and the resuscitation phase. Major alterations were observed in plasma concentrations of metabolites related to tricarboxylic acid (TCA) cycle, urea cycle, and anaplerotic replenishing of TCA. ACA animals showed significant metabolic disturbances during the asphyxial and CA phases, while for VFCA animals this phenomenon resulted shifted at the resuscitation phase. Interestingly, starting from the asphyxial phase, the ACA animals were stratified in two groups based on their metabolomics profiles that resulted to be correlated with the clinical outcome. Succinate overproduction was observed in the animals with the worse outcome, suggesting a potential prognostic role for this metabolite.

3.
J Inorg Biochem ; 177: 101-109, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28946026

RESUMO

Coumarins show biological activity and are widely exploited for their therapeutic effects. Although a great number of coumarins substituted by heterocyclic moieties have been prepared, few studies have been carried out on coumarins containing pyridine heterocycle, which is known to modulate their physiological activities. We prepared and characterized three novel 3-(pyridin-2-yl)coumarins and their corresponding copper(II) complexes. We extended our investigations also to three known similar coumarins, since no data about their biochemical activity was previously been reported. The antiproliferative activity of the studied compounds was tested against human derived tumor cell lines and one human normal cell line. The DNA binding constants were determined and docking studies with DNA carried out. Selected Quantitative Structure-Activity Relationship (QSAR) descriptors were calculated in order to relate a set of structural and topological descriptors of the studied compounds to their DNA interaction and cytotoxic activity.


Assuntos
Antineoplásicos/farmacologia , Complexos de Coordenação/farmacologia , Cobre/química , Cumarínicos/farmacologia , DNA/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/toxicidade , Linhagem Celular Tumoral , Complexos de Coordenação/síntese química , Complexos de Coordenação/química , Complexos de Coordenação/toxicidade , Cumarínicos/síntese química , Cumarínicos/química , Cumarínicos/toxicidade , Humanos , Ligantes , Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade
4.
ChemistryOpen ; 4(2): 161-8, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25969814

RESUMO

The aim of this study is to describe and compare the supramolecular interactions, in the solid state, of chloro-, bromo-, and iodobenzothiophene diols. The compounds were obtained through organo-catalyzed reactions starting from 3-substituted halobenzothiophene carbaldehydes. Energies of the noncovalent interactions were obtained by density functional theory calculations. Bond distances and angles were found to be in accordance with those determined by X-ray structure analysis. anti-Bromobenzothiophene derivatives showed strong halogen⋅⋅⋅π interactions between bromine and the heterocyclic phenyl ring, corresponding to an energy of 7.5 kcal mol(-1). syn-Bromo and syn-iodo derivatives appeared to be isostructural, showing X⋅⋅⋅O (carbonyl) interactions, π stacking, and formation of extended hydrogen bonding networks. In contrast, the chloro derivatives displayed no halogen bonding interactions.

5.
ChemMedChem ; 8(6): 956-66, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23589499

RESUMO

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Several 3-arylcoumarin derivatives were previously described as interesting selective MAO-B inhibitors. Preserving the trans-stilbene structure, a series of 2-arylbenzofuran and corresponding 3-arylcoumarin derivatives were synthesized and evaluated as inhibitors of both MAO isoforms, MAO-A and MAO-B. In general, both types of derivatives were found to be selective MAO-B inhibitors, with IC50 values in the nano- to micromolar range. 5-Nitro-2-(4-methoxyphenyl)benzofuran (8) is the most active compound of the benzofuran series, presenting MAO-B selectivity and reversible inhibition (IC50 =140 nM). 3-(4'-Methoxyphenyl)-6-nitrocoumarin (15), with the same substitution pattern as that of compound 8, was found to be the most active MAO-B inhibitor of the coumarin series (IC50 =3 nM). However, 3-phenylcoumarin 14 showed activity in the same range (IC50 =6 nM), is reversible, and also severalfold more selective than compound 15. Docking experiments for the most active compounds into the MAO-B and MAO-A binding pockets highlighted different interactions between the derivative classes (2-arylbenzofurans and 3-arylcoumarins), and provided new information about the enzyme-inhibitor interaction and the potential therapeutic application of these scaffolds.


Assuntos
Benzofuranos/farmacologia , Cumarínicos/farmacologia , Inibidores Enzimáticos/farmacologia , Monoaminoxidase/metabolismo , Benzofuranos/síntese química , Benzofuranos/química , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
6.
Curr Top Med Chem ; 12(20): 2145-62, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23231393

RESUMO

The number of papers dealing with the structure-based drug design is continuously growing, which demonstrates the importance of such tools in medicinal chemistry. In the current paper, the published literature concerning the use of the ligand-protein docking methodologies in the study of the monoamine oxidase (MAO) enzymes was reviewed. Ten years of studies aimed at developing new compounds active as MAO inhibitors (MAOIs) were covered. The literature regarding thiazole, caffeine, pyrazole, chromone, indeno-pyridazin, ß-carboline, indole, coumarin, anilide and amphetamine derivatives, was discussed in some detail. It is apparent that, through this computational approach, more selective and potent molecules can be proposed as inhibitors by applying precise modifications on the basic scaffold.


Assuntos
Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Cristalografia por Raios X , Desenho de Drogas , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Monoaminoxidase/química , Inibidores da Monoaminoxidase/química , Relação Estrutura-Atividade
7.
Curr Top Med Chem ; 12(20): 2258-74, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23231398

RESUMO

The evolution of bio- and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that "similar molecules have similar biological properties" that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure- Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes' function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer's and Parkinson's disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action.


Assuntos
Modelos Químicos , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Humanos , Ligantes , Modelos Moleculares , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/uso terapêutico , Doenças Neurodegenerativas/enzimologia , Doenças Neurodegenerativas/metabolismo , Relação Quantitativa Estrutura-Atividade
8.
ChemMedChem ; 7(3): 464-70, 2012 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-22287164

RESUMO

Neurodegenerative disorders are becoming more prevalent given the increase in the aging population. This has inspired active research in the development of new drugs that could mark an important advance in the treatment of complex diseases such as Alzheimer's and Parkinson's. With the aim of finding new MAO-B-selective inhibitors, we report the synthesis, in vitro evaluation, and docking simulation of a new series of 3-arylcoumarins variously substituted at the 8-position. Most of the studied compounds show high affinity and selectivity for the hMAO-B isoform, with IC50 values in the low micro- to nanomolar range. Some of them have greater hMAO-B inhibitory activity and selectivity than the reference compound, selegiline. Compounds 7 and 8 are the most active of this series, with compound 8 being fivefold more potent against MAO-B and severalfold more selective than selegiline. Docking experiments were carried out with hMAO-B crystal structures, providing new information about the enzyme-inhibitor interaction and the potential therapeutic application of the new 8-substituted 3-arylcoumarins.


Assuntos
Cumarínicos/síntese química , Inibidores da Monoaminoxidase/síntese química , Monoaminoxidase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Cumarínicos/farmacologia , Humanos , Modelos Moleculares , Inibidores da Monoaminoxidase/farmacologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Ligação Proteica , Isoformas de Proteínas/metabolismo , Selegilina/farmacologia , Soluções
9.
Bioorg Med Chem Lett ; 22(1): 258-61, 2012 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-22137786

RESUMO

A series of 3-aryl-4-hydroxycoumarin derivatives was synthesized with the aim to find out the structural features for the MAO inhibitory activity and selectivity. Methoxy and/or chloro substituents were introduced in the 3-phenyl ring, whereas the position 6 in the coumarin moiety was not substituted or substituted with a methyl group or a chloro atom due to their different electronic, steric and/or lipophilic properties. Most of the synthesized compounds presented MAO-B inhibitory activity. The presence of methoxy and chloro groups, respectively in the para and meta positions of the 3-phenyl ring, have an important influence on the inhibitory activity. Moreover, the presence of a chloro atom in the six position of the moiety (compound 7) improved the inhibitor activity as well as its selectivity against MAO-B compared with iproniazide, used as reference compound. Docking experiments were carried out to understand which are the most energetically preferred orientations adopted by compounds 5, 6 and 7 inside the MAO-B binding pocket.


Assuntos
4-Hidroxicumarinas/farmacologia , Química Farmacêutica/métodos , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/química , Animais , Azidas/farmacologia , Sítios de Ligação , Simulação por Computador , Desenho de Drogas , Humanos , Concentração Inibidora 50 , Espectroscopia de Ressonância Magnética , Modelos Químicos , Eletricidade Estática , Relação Estrutura-Atividade , Termodinâmica
10.
ChemMedChem ; 6(8): 1452-8, 2011 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-21598398

RESUMO

Cytidine deaminase (EC 3.5.4.5, CDA), an enzyme of the pyrimidine salvage pathways, is responsible for the degradation and inactivation of several cytidine-based antitumor drugs such as cytarabine, gemcitabine, decitabine, and azacytidine. Thus, CDA inhibitors are highly sought after as compounds to be co-administered with said drugs to improve their effectiveness. Alternatively, the design of antitumor drugs not susceptible to the action of CDA is also regarded as an attractive solution. Herein we describe a virtual screen for CDA ligands based on chemical similarity and molecular docking. The campaign led to the identification of three novel inhibitors and one novel substrate, with a 19 % hit rate, and allowed a significant extension of the structure-activity relationships, also in light of the compounds that resulted inactive. The most active compound identified through the screen is the inhibitor pseudoisocytidine, which has the potential to serve as a lead for highly stable compounds. The study also delineated the detrimental effect of 5-aza and 6-aza substitutions, the incompatibility of the presence of an amino group at the 3'-position, as well as the presence of very strict steric requirements around the 2'-arabino position and, even more, the N4-position. Importantly, these features can be exploited for the design of novel anti-neoplastic agents resistant to the action of CDA.


Assuntos
Antineoplásicos/química , Citidina Desaminase/antagonistas & inibidores , Inibidores Enzimáticos/química , Nucleosídeos/química , Animais , Antineoplásicos/farmacologia , Sítios de Ligação , Citidina/análogos & derivados , Citidina/farmacologia , Citidina Desaminase/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Cinética , Camundongos , Simulação de Dinâmica Molecular , Nucleosídeos/síntese química , Nucleosídeos/farmacologia , Relação Estrutura-Atividade
11.
Eur J Med Chem ; 46(4): 1147-52, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21316817

RESUMO

Monoamine oxidase (MAO) is an important drug target for the treatment of neurological disorders. Series of 3-indolyl and 3-thiophenylcoumarins were synthesized and evaluated as inhibitors of the two human MAO isoforms, hMAO-A and hMAO-B. In general, the derivatives were found to be selective hMAO-B inhibitors with IC(50) values in the nanoMolar (nM) to microMolar (µM) range. Docking experiments were carried out in order to compare the theoretical and experimental affinity of these compounds to the hMAO-B protein. According to our results, docking experiments could be an interesting approach to try to predict the activity of this class of coumarins against MAO-B receptors.


Assuntos
Cumarínicos/síntese química , Cumarínicos/farmacologia , Modelos Moleculares , Inibidores da Monoaminoxidase/síntese química , Inibidores da Monoaminoxidase/farmacologia , Monoaminoxidase/metabolismo , Cumarínicos/química , Cumarínicos/metabolismo , Humanos , Monoaminoxidase/química , Inibidores da Monoaminoxidase/química , Inibidores da Monoaminoxidase/metabolismo , Conformação Proteica
12.
J Mol Graph Model ; 29(5): 614-23, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21146435

RESUMO

G protein-coupled receptors (GPCRs) regulate a wide range of physiological functions and hold great pharmaceutical interest. Using the ß(2)-adrenergic receptor as a case study, this article explores the applicability of docking-based virtual screening to the discovery of GPCR ligands and defines methods intended to improve the screening performance. Our controlled computational experiments were performed on a compound dataset containing known agonists and blockers of the receptor as well as a large number of decoys. The screening based on the structure of the receptor crystallized in complex with its inverse agonist carazolol yielded excellent results, with a clearly delineated prioritization of ligands over decoys. Blockers generally were preferred over agonists; however, agonists were also well distinguished from decoys. A method was devised to increase the screening yields by generating an ensemble of alternative conformations of the receptor that accounts for its flexibility. Moreover, a method was devised to improve the retrieval of agonists, based on the optimization of the receptor around a known agonist. Finally, the applicability of docking-based virtual screening also to homology models endowed with different levels of accuracy was proved. This last point is of uttermost importance, since crystal structures are available only for a limited number of GPCRs, and extends our conclusions to the entire superfamily. The outcome of this analysis definitely supports the application of computer-aided techniques to the discovery of novel GPCR ligands, especially in light of the fact that, in the near future, experimental structures are expected to be solved and become available for an ever increasing number of GPCRs.


Assuntos
Simulação por Computador , Modelos Moleculares , Conformação Proteica , Receptores Acoplados a Proteínas-G/química , Agonistas de Receptores Adrenérgicos beta 2/química , Antagonistas de Receptores Adrenérgicos beta 2/química , Desenho de Drogas , Ligantes , Estrutura Molecular , Receptores Adrenérgicos beta 2/química , Receptores Adrenérgicos beta 2/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo
13.
Biochem Biophys Res Commun ; 372(2): 320-5, 2008 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-18503754

RESUMO

In prostate cancer (PCa), prognostic (predictive) factors are particularly important given the marked heterogeneity of this disease at clinical, morphologic, and biomolecular levels. Blood contains a treasure of previously unstudied biomarkers that could reflect the ongoing physiological state of all tissue. The serum prostate-specific antigen (PSA) measurement is a very good biomarker for PCa, but the percentage of bad classification is somewhat high. The blood proteome mass spectra (MS) represent a potential tool for detection of diseases; however the identification of a single biomarker from the complex output from MS is often difficult. In this paper, we propose a general strategy, based on computational chemistry techniques, which should improve the predictive power of PSA. Our group adapted the square-spiral graph to represent human serum-plasma-proteome MS for healthy and PCa patients. These graphs were previously applied to DNA and/or protein sequences. In this work, we calculated different classes of connectivity indices (CIs), and created various models based on the spectral moments. The best QPDRs model found showed accuracy values ranging from 71.7% to 97.2%, and 70.4% to 99.2% of specificity. This methodology might be useful for several applications in computational chemistry.


Assuntos
Biomarcadores Tumorais/sangue , Espectrometria de Massas/métodos , Antígeno Prostático Específico/sangue , Neoplasias da Próstata/sangue , Neoplasias da Próstata/diagnóstico , Proteoma , Humanos , Masculino , Prognóstico
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