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1.
Nature ; 581(7808): 288-293, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32433618

RESUMO

The hydrogen isotopes deuterium (D) and tritium (T) have become essential tools in chemistry, biology and medicine1. Beyond their widespread use in spectroscopy, mass spectrometry and mechanistic and pharmacokinetic studies, there has been considerable interest in incorporating deuterium into drug molecules1. Deutetrabenazine, a deuterated drug that is promising for the treatment of Huntington's disease2, was recently approved by the United States' Food and Drug Administration. The deuterium kinetic isotope effect, which compares the rate of a chemical reaction for a compound with that for its deuterated counterpart, can be substantial1,3,4. The strategic replacement of hydrogen with deuterium can affect both the rate of metabolism and the distribution of metabolites for a compound5, improving the efficacy and safety of a drug. The pharmacokinetics of a deuterated compound depends on the location(s) of deuterium. Although methods are available for deuterium incorporation at both early and late stages of the synthesis of a drug6,7, these processes are often unselective and the stereoisotopic purity can be difficult to measure7,8. Here we describe the preparation of stereoselectively deuterated building blocks for pharmaceutical research. As a proof of concept, we demonstrate a four-step conversion of benzene to cyclohexene with varying degrees of deuterium incorporation, via binding to a tungsten complex. Using different combinations of deuterated and proteated acid and hydride reagents, the deuterated positions on the cyclohexene ring can be controlled precisely. In total, 52 unique stereoisotopomers of cyclohexene are available, in the form of ten different isotopologues. This concept can be extended to prepare discrete stereoisotopomers of functionalized cyclohexenes. Such systematic methods for the preparation of pharmacologically active compounds as discrete stereoisotopomers could improve the pharmacological and toxicological properties of drugs and provide mechanistic information related to their distribution and metabolism in the body.


Assuntos
Benzeno/química , Técnicas de Química Sintética , Cicloexenos/química , Cicloexenos/síntese química , Deutério/química , Preparações Farmacêuticas/química , Preparações Farmacêuticas/síntese química , Bases de Dados de Compostos Químicos , Cinética , Estrutura Molecular , Estereoisomerismo , Tetrabenazina/análogos & derivados , Tetrabenazina/síntese química , Tetrabenazina/química , Tungstênio/química
2.
FEBS Open Bio ; 10(6): 995-1004, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32374074

RESUMO

A novel coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or 2019 novel coronavirus] has been identified as the pathogen of coronavirus disease 2019. The main protease (Mpro , also called 3-chymotrypsin-like protease) of SARS-CoV-2 is a potential target for treatment of COVID-19. A Mpro homodimer structure suitable for docking simulations was prepared using a crystal structure (PDB ID: 6Y2G; resolution 2.20 Å). Structural refinement was performed in the presence of peptidomimetic α-ketoamide inhibitors, which were previously disconnected from each Cys145 of the Mpro homodimer, and energy calculations were performed. Structure-based virtual screenings were performed using the ChEMBL database. Through a total of 1 485 144 screenings, 64 potential drugs (11 approved, 14 clinical, and 39 preclinical drugs) were predicted to show high binding affinity with Mpro . Additional docking simulations for predicted compounds with high binding affinity with Mpro suggested that 28 bioactive compounds may have potential as effective anti-SARS-CoV-2 drug candidates. The procedure used in this study is a possible strategy for discovering anti-SARS-CoV-2 drugs from drug libraries that may significantly shorten the clinical development period with regard to drug repositioning.


Assuntos
Betacoronavirus/enzimologia , Quimases/metabolismo , Infecções por Coronavirus/metabolismo , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/métodos , Preparações Farmacêuticas/metabolismo , Pneumonia Viral/metabolismo , Inibidores de Serino Proteinase/metabolismo , Proteínas Virais/metabolismo , Betacoronavirus/efeitos dos fármacos , Domínio Catalítico , Quimases/antagonistas & inibidores , Quimases/química , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cristalização , Bases de Dados de Compostos Químicos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pandemias , Preparações Farmacêuticas/química , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Inibidores de Serino Proteinase/química , Proteínas Virais/química
3.
Mar Drugs ; 18(4)2020 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-32340389

RESUMO

The current emergency due to the worldwide spread of the COVID-19 caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a great concern for global public health. Already in the past, the outbreak of severe acute respiratory syndrome (SARS) in 2003 and Middle Eastern respiratory syndrome (MERS) in 2012 demonstrates the potential of coronaviruses to cross-species borders and further underlines the importance of identifying new-targeted drugs. An ideal antiviral agent should target essential proteins involved in the lifecycle of SARS-CoV. Currently, some HIV protease inhibitors (i.e., Lopinavir) are proposed for the treatment of COVID-19, although their effectiveness has not yet been assessed. The main protease (Mpr) provides a highly validated pharmacological target for the discovery and design of inhibitors. We identified potent Mpr inhibitors employing computational techniques that entail the screening of a Marine Natural Product (MNP) library. MNP library was screened by a hyphenated pharmacophore model, and molecular docking approaches. Molecular dynamics and re-docking further confirmed the results obtained by structure-based techniques and allowed this study to highlight some crucial aspects. Seventeen potential SARS-CoV-2 Mpr inhibitors have been identified among the natural substances of marine origin. As these compounds were extensively validated by a consensus approach and by molecular dynamics, the likelihood that at least one of these compounds could be bioactive is excellent.


Assuntos
Antivirais/farmacologia , Betacoronavirus/enzimologia , Infecções por Coronavirus , Pandemias , Pneumonia Viral , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Antivirais/química , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Produtos Biológicos/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cisteína Endopeptidases , Bases de Dados de Compostos Químicos , Humanos , Modelos Moleculares , Simulação de Acoplamento Molecular , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Inibidores de Proteases/química , Inibidores de Proteases/uso terapêutico
5.
Nat Commun ; 11(1): 727, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-32024839

RESUMO

As plastic marine debris continues to accumulate in the oceans, many important questions surround this global dilemma. In particular, how many descriptors would be necessary to model the degradation behavior of ocean plastics or understand if degradation is possible? Here, we report a data-driven approach to elucidate degradation trends of plastic debris by linking abiotic and biotic degradation behavior in seawater with physical properties and molecular structures. The results reveal a hierarchy of predictors to quantify surface erosion as well as combinations of features, like glass transition temperature and hydrophobicity, to classify ocean plastics into fast, medium, and slow degradation categories. Furthermore, to account for weathering and environmental factors, two equations model the influence of seawater temperature and mechanical forces.


Assuntos
Plásticos/química , Poluentes Químicos da Água/química , Biodegradação Ambiental , Biotransformação , Bases de Dados de Compostos Químicos , Interações Hidrofóbicas e Hidrofílicas , Aprendizado de Máquina , Modelos Teóricos , Peso Molecular , Plásticos/metabolismo , Água do Mar/química , Temperatura , Poluentes Químicos da Água/metabolismo
6.
Mutat Res ; 849: 503137, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-32087853

RESUMO

The International Workshop on Genotoxicity Testing (IWGT) meets every four years to obtain consensus on unresolved issues associated with genotoxicity testing. At the 2017 IWGT meeting in Tokyo, four sub-groups addressed issues associated with the Organization for Economic Cooperation and Development (OECD) Test Guideline TG471, which describes the use of bacterial reverse-mutation tests. The strains sub-group analyzed test data from >10,000 chemicals, tested additional chemicals, and concluded that some strains listed in TG471 are unnecessary because they detected fewer mutagens than other strains that the guideline describes as equivalent. Thus, they concluded that a smaller panel of strains would suffice to detect most mutagens. The laboratory proficiency sub-group recommended (a) establishing strain cell banks, (b) developing bacterial growth protocols that optimize assay sensitivity, and (c) testing "proficiency compounds" to gain assay experience and establish historical positive and control databases. The sub-group on criteria for assay evaluation recommended that laboratories (a) track positive and negative control data; (b) develop acceptability criteria for positive and negative controls; (c) optimize dose-spacing and the number of analyzable doses when there is evidence of toxicity; (d) use a combination of three criteria to evaluate results: a dose-related increase in revertants, a clear increase in revertants in at least one dose relative to the concurrent negative control, and at least one dose that produced an increase in revertants above control limits established by the laboratory from historical negative controls; and (e) establish experimental designs to resolve unclear results. The in silico sub-group summarized in silico utility as a tool in genotoxicity assessment but made no specific recommendations for TG471. Thus, the workgroup identified issues that could be addressed if TG471 is revised. The companion papers (a) provide evidence-based approaches, (b) recommend priorities, and (c) give examples of clearly defined terms to support revision of TG471.


Assuntos
Escherichia coli/efeitos dos fármacos , Mutagênese , Testes de Mutagenicidade/normas , Mutagênicos/toxicidade , Salmonella typhimurium/efeitos dos fármacos , Animais , Bancos de Espécimes Biológicos/organização & administração , Bases de Dados de Compostos Químicos/provisão & distribução , Escherichia coli/genética , Guias como Assunto , Humanos , Cooperação Internacional , Mutagênicos/classificação , Salmonella typhimurium/genética , Tóquio
7.
J Chem Theory Comput ; 16(2): 1359-1366, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31935088

RESUMO

Protein backbone torsion angles (Phi and Psi) are crucial for protein local conformation description. In this paper, we propose a general postprocessing method for all prediction methods, namely, OPUS-Refine, which may contribute to the field in a different way. OPUS-Refine is a sampling-based method, therefore, the results of other prediction methods can be used as its constraints. After OPUS-Refine refinement, for instance, the accuracy of Phi/Psi predicted by SPIDER3 and SPOT-1D are both increased. In addition, to facilitate the sampling efficiency, we construct a neighbor-dependent statistical torsion angles sampling database, namely, OPUS-TA, which may be useful for other sampling-based methods. Furthermore, we also introduce the contact map predicted by RaptorX to OPUS-Refine as a global structural constraint. After refinement, compared to the predicted structures obtained from RaptorX online server, the accuracy of both global structural configurations (measured by TM-score and RMSD) and local structural configurations (measured by Phi/Psi) results are improved. OPUS-Refine is a highly efficient framework, it takes only about 4 s to refine the torsion angles and 30 s to refine the global structure of a protein with 100 residues in length on a typical desktop personal computer. Therefore, the sampling-based feature and the efficiency of OPUS-Refine offer greater potentiality for it to take advantage of any other method to achieve better performance.


Assuntos
Simulação por Computador , Bases de Dados de Compostos Químicos , Modelos Químicos , Proteínas/química , Modelos Moleculares , Redes Neurais de Computação , Conformação Proteica
8.
J Chromatogr A ; 1617: 460841, 2020 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31954542

RESUMO

The solvation parameter model is a well established quantitative structure-property relationship model suitable for describing the contribution of intermolecular interactions in a wide range of separation, chemical, biological and environmental processes. The model employs six descriptors for neutral compounds to describe their capability to interact with their environment of which only one, McGowan's characteristic volume (V) is available by calculation for compounds with a known structure. The other five descriptors are derived from experimental data, the refractive index at 20 °C for the excess molar refraction (E), at least for liquids, and the dipolarity/polarizability (S), hydrogen-bond acidity or basicity (A and B) and gas-liquid partition constant on n-hexadecane at 25 °C (L) typically from chromatographic measurements using gas, liquid or micellar electrokinetic chromatography, liquid-liquid partition, or solubility. In this article a descriptor database is assembled utilizing gas and reversed-phase liquid chromatography retention factors and liquid-liquid partition constants determined in a single laboratory to facilitate control over the experimental techniques employed together with a general set of selection tools to identify systems likely to result in unreliable experimental values for specific compounds. The assembled descriptors for a wide range of varied compounds are expected to be more robust for characterizing separation systems than those currently in use.


Assuntos
Bases de Dados de Compostos Químicos , Modelos Químicos , Cromatografia Gasosa , Cromatografia de Fase Reversa , Ligação de Hidrogênio , Relação Quantitativa Estrutura-Atividade , Solubilidade
9.
Food Chem Toxicol ; 135: 110921, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31669597

RESUMO

Determining chemical carcinogenicity in the early stages of drug discovery is fundamentally important to prevent the adverse effect of carcinogens on human health. There has been a recent surge of interest in developing computational approaches to predict chemical carcinogenicity. However, the predictive power of many existing approaches is limited, and there is plenty of room for improvement. Here, we develop a new deep learning architecture, termed CapsCarcino, to distinguish between carcinogens and noncarcinogens. CapsCarcino is constructed based on a dynamic routing algorithm that requires less data, extracts more comprehensive information, and does not require feature selection. We find that CapsCarcino provides a significantly improved predictive and generalization ability over, and outperforms five other machine learning models. Specifically, the best model of CapsCarcino achieves an accuracy of 85.0% on an external validation dataset. In addition, we discover that the enhanced predictive capability of CapsCarcino over that of the other methods is robust and can be achieved using sparse datasets. Training on merely 20% of the dataset, CapsCarcino performs comparably to the other methods based on the full training dataset. Further mechanism analysis indicates that CapsCarcino could efficiently learn the characteristics of carcinogens even if structural alerts are insufficiently represented. The results indicate that CapsCarcino should be helpful for carcinogen risk assessment.


Assuntos
Carcinógenos/química , Aprendizado Profundo , Animais , Bases de Dados de Compostos Químicos/estatística & dados numéricos , Ratos
10.
Biochimie ; 168: 220-230, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31756401

RESUMO

G9a (also known as EHMT2 - Euchromatin histone methyltransferase 2) is a protein lysine methyltransferase which introduces methylation modification in variety of proteins including histones. G9a catalyzes the dimethylation of lysine 9 on histone 3 (H3K9me2) which is a repressive epigenetic modification. H3K9me2 is associated with the silencing of several genes including tumor suppressor genes in many cancers and hence G9a is a well characterized drug target for cancer therapy. Here, we report the discovery of CSV0C018875 as a novel quinoline based G9a inhibitor through virtual screening strategy from a HTS database. Sub-structure querying based on the known G9a inhibitors, followed by docking based virtual screening, led to the identification of CSV0C018875 as G9a inhibitor. We found that CSV0C018875 inhibits the activity of G9a in both enzyme and cell based assays. Importantly, the toxicity of CSV0C018875 is much lesser than that of the well-studied G9a inhibitor, BIX-01294. Molecular dynamics simulations shows that CSV0C018875 binds deeper inside the active site cavity of G9a, which facilitates the tight binding and also increases the compounds residence time, which in turn reflects better G9a inhibition. The novel quinoline CSV0C018875 could be further optimized to improve the ADME as well pharmacodynamic property.


Assuntos
Inibidores Enzimáticos , Antígenos de Histocompatibilidade , Histona-Lisina N-Metiltransferase , Quinolinas , Azepinas/química , Domínio Catalítico , Bases de Dados de Compostos Químicos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Células HEK293 , Antígenos de Histocompatibilidade/metabolismo , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/metabolismo , Histonas/metabolismo , Humanos , Metilação , Ligação Proteica , Quinazolinas/química , Quinolinas/química , Quinolinas/metabolismo
11.
SAR QSAR Environ Res ; 31(3): 171-186, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31858821

RESUMO

The European Registration, Evaluation, Authorization and Restriction of Chemical Substances Regulation, requires marketed chemicals to be evaluated for Ready Biodegradability (RB), considering in silico prediction as valid alternative to experimental testing. However, currently available models may not be relevant to predict compounds of industrial interest, due to accuracy and applicability domain restriction issues. In this work, we present a new and extended RB dataset (2830 compounds), issued by the merging of several public data sources. It was used to train classification models, which were externally validated and benchmarked against already-existing tools on a set of 316 compounds coming from the industrial context. New models showed good performances in terms of predictive power (Balance Accuracy (BA) = 0.74-0.79) and data coverage (83-91%). The Generative Topographic Mapping approach identified several chemotypes and structural motifs unique to the industrial dataset, highlighting for which chemical classes currently available models may have less reliable predictions. Finally, public and industrial data were merged into global dataset containing 3146 compounds. This is the biggest dataset reported in the literature so far, covering some chemotypes absent in the public data. Thus, predictive model developed on the Global dataset has larger applicability domain than the existing ones.


Assuntos
Bases de Dados de Compostos Químicos , Poluentes Ambientais/química , Modelos Químicos , Algoritmos , Benchmarking , Biodegradação Ambiental , Simulação por Computador , Bases de Dados de Compostos Químicos/normas , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes
20.
J Chem Ecol ; 45(11-12): 914-925, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31802386

RESUMO

Frogs in the genus Phyllobates are known for the presence of batrachotoxin, a highly toxic alkaloid, in their skin. Nevertheless, Phyllobates frogs from Costa Rica and Panama (P. lugubris and P. vittatus) are considered non-toxic, as they have been reported to harbor low concentrations of this alkaloid. However, the potential toxicity of Central American Phyllobates has not been assessed experimentally. Our goal was to determine the toxicity of the whole skin of P. vittatus, an endemic species from the Southeastern Pacific region of Costa Rica. We performed median lethal dose (LD50) tests in mice to determine general toxicity, and an irritant assay based on the behavioral responses of mice to subcutaneous injection, to determine differences in irritability, as a measure of toxicity, among three study localities. Using UPLC-ESI-QTOF, we obtained chemical profiles of the methanolic extract of frog skins. Due to the absence of mortality at the studied doses, we were unable to estimate LD50. However, we recorded a list of toxicity symptoms in mice that are consistent with cardiotoxic effects, and found that mice presented more symptoms at higher concentrations of skin extracts during the first hour of the LD50 assays, recovering completely at all doses by the end of the assay. On the other hand, we did not detect differences in irritability among studied localities. Additionally, we putatively identified three toxic alkaloids (Batrachotoxinin A, DHQ 251A and Lehm 275A). This study provides the first experimental data on the toxicity and associated symptoms in mice, as well as the chemical profile of the skin of P. vittatus. We suggest that the skin alkaloids of P. vitattus may confer a chemical defense towards predators.


Assuntos
Alcaloides/análise , Alcaloides/toxicidade , Anuros/fisiologia , Misturas Complexas/análise , Misturas Complexas/toxicidade , Pele/química , Animais , Cromatografia Líquida de Alta Pressão/métodos , Simulação por Computador , Costa Rica , Bases de Dados de Compostos Químicos , Feminino , Dose Letal Mediana , Camundongos Endogâmicos ICR , Venenos/análise , Venenos/toxicidade , Espectrometria de Massas em Tandem/métodos
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