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1.
J Chromatogr A ; 1629: 461501, 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-32841768

RESUMO

Metabolic stability tests are one of the fundamental steps at the preclinical stages of new drug development. Microsomes, used as a typical enzymatic model of liver biotransformation, can be a challenging matrix for analytical scientists due to a high concentration of cellular proteins and membrane lipids. In the work, we propose a new procedure integrating biotransformation reaction with SPME-like protocol for sample clean-up. It is beneficial to increase the overall quality of results in contrary to the typical protein precipitation approach. A set of ten arylpiperazine analogs, six of which are considered promising drug candidates (and four are accepted drugs) were used as a probe to assess the goodness of the newly proposed approach. In order to promote an efficient extraction protocol, a new, miniaturized shape of a sorbent, suitable to perform the extraction in 100 µL of the sample has been designed. Termination of the biotransformation process by protein denaturation with hot water was additionally evaluated. A quantitative structure-property relationship (QSPR) study using Orthogonal Partial Least Squares (OPLS) technique to reveal insights to the sorption mechanism was also performed. The obtained results showed the new 3D-printed sorbent can be an attractive basis for the new sample preparation approach for metabolic stability studies and an alternative for commercially available protocols based on solid-phase microextraction (SPME) or solid-phase extraction (SPE) principles.


Assuntos
Preparações Farmacêuticas/química , Impressão Tridimensional , Adsorção , Análise dos Mínimos Quadrados , Preparações Farmacêuticas/isolamento & purificação , Relação Quantitativa Estrutura-Atividade , Microextração em Fase Sólida
2.
J Chromatogr A ; 1626: 461388, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32797859

RESUMO

A reversed-phase high performance liquid chromatographic method was developed and validated for the simultaneous determination of the related substances of S-dapoxetine, including R-dapoxetine, (3S)-3-(dimethylamino-3-phenyl-1-propanol), S-3-amino-3-phenyl-1-propanol, 1-naphtol, 4-phenyl-2H,3H,4H-naphtho[1,2-b]pyran and 1-(2E)-Cinnamyloxynaphthalene. During the screening experiments seven different polysaccharide-type chiral stationary phases (amylose-based Lux-Amylose-1, Lux-i-Amylose-1 and Lux-Amylose-2, as well as cellulose-based Lux-Cellulose-1, Lux-Cellulose-2, Lux-Cellulose-3 and Lux-Cellulose-4) were tested in polar organic mode using a mobile phase consisting of 0.1% diethylamine in methanol, ethanol, 2-propanol and acetonitrile with 0.5 mL min-1 flow rate at 20 °C. Best results were obtained on Lux Cellulose-3 column with the ethanol-based mobile phase. To increase the retention factor of two, early-eluting impurities, water was added to the mobile phase. In order to counterbalance the increased total analysis time, higher column temperature (40 °C) and gradient elution, combined with flow-programming` was applied. Using the optimized conditions baseline separations were achieved for all compounds within 30 min. The method was validated according to the International Council on Harmonization guideline Q2(R1) and applied to the analysis of an approved, tablet formulation and dapoxetine-containing products sold on the internet. As expected, in the case of the pharmacy-acquired product, all of the monitored impurities were below 0.1%. However, interesting results were obtained when internet-acquired samples were analyzed. These tablets contained racemic dapoxetine and/or high concentration of R-dapoxetine impurity. Based on this work polysaccharide-based chiral stationary phases can be successfully applied for the simultaneous determination of achiral and chiral impurities in reversed-phase mode applying gradient elution and flow-rate programs. The study further underlines the importance of not only achiral, but also enantiomeric quality control, whenever counterfeiting of a single enantiomeric agent is suspected.


Assuntos
Benzilaminas/análise , Cromatografia Líquida de Alta Pressão/métodos , Naftalenos/análise , Cromatografia de Fase Reversa , Limite de Detecção , Espectrometria de Massas , Preparações Farmacêuticas/química , Estereoisomerismo , Comprimidos/química , Temperatura
3.
Emerg Top Life Sci ; 4(2): 175-177, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32856697

RESUMO

Precision medicine can be defined as personalized medicine enhanced by technology. In the past, medicine has, in some cases, been personalized. For example, some drugs are dosed on an individualized basis based on age, body-mass index, comorbidities and other clinical parameters. However, overall, medicine has largely followed the 'one-size-fits-all' paradigm as exemplified in the treatment of essential hypertension or type 2 diabetes mellitus. What has changed in the past few years is that technologies such as high throughput sequencing, mass spectrometry, microfluidics, and imaging can help conduct a multitude of complex measurements on clinical samples. Aided by analytics, these technologies have been providing an increasingly detailed picture of molecular and cellular alterations underlying numerous diseases and have revealed tremendous variability between individuals and patients at the molecular and cellular level. These findings have motivated a more personalized or 'precision' approach to medicine, in which molecular and cellular markers help tailor patient management to each individual. Here we provide an overview of the key factors driving adoption of precision medicine and highlight current research that may soon make precision medicine more predictive.


Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Hipertensão/diagnóstico , Hipertensão/terapia , Medicina de Precisão/métodos , Biomarcadores/metabolismo , Gerenciamento Clínico , Previsões , Predisposição Genética para Doença , Genômica , Humanos , Terapia de Alvo Molecular , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo
4.
J Chromatogr A ; 1628: 461425, 2020 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-32861181

RESUMO

A new broadly applicable achiral-chiral 2-dimensional heart-cutting (LC-LC) platform is designed comprising a multi-column selection approach in the chiral dimension. As both dimensions are operated in a highly aqueous reversed-phase type mode, analysis of a broad range of pharmaceutical solutes (LogP: 1.49-5.7) and their impurities becomes possible, while breakthrough issues arising due to solvent immiscibility and peak broadening phenomena in the second dimension are practically circumvented. These aspects, together with the chromatographic and quantitative performances are systematically assessed for various transfer loop sizes (50, 100, 200 and 500 µl), column diameters (2.0 and 4.6 mm), and various gradients (10, 20 and 40 min) with a mixture of five racemates covering a broad range in polarity. In order to broaden the selectivity of the second dimension, an automated chiral screening is performed comprising six chiral columns, allowing baseline separation for all enantiomers and a chiral resolution up to 17.21 for some of the racemates. The performance of the platform is also assessed in pharmaceutical drug development samples. A hybrid high-resolution (HiRes) sample approach is thereby used, which proves to be effective for precise confirmation of the relative prevalence of the impurities compared to the principal compound in all studied cases. The co-eluted impurities were thereby effectively detected and quantified down to the 0.05% level. The obtained figures of merits indicate the suitability of the platform for implementation in industry.


Assuntos
Cromatografia Líquida/métodos , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/química , Solventes , Estereoisomerismo , Fatores de Tempo
5.
Nat Commun ; 11(1): 4170, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32820174

RESUMO

Sulfur-sulfur motifs widely occur in vital function and drug design, which yearns for polysulfide construction in an efficient manner. However, it is a great challenge to install desired functional groups on both sides of sulfur-sulfur bonds at liberty. Herein, we designed a mesocyclic bilateral disulfurating reagent for sequential assembly and modular installation of polysulfides. Based on S-O bond dissociation energy imparity (mesocyclic compared to linear imparity is at least 5.34 kcal mol-1 higher), diverse types of functional molecules can be bridged via sulfur-sulfur bonds distinctly. With these stable reagents, excellent reactivities with nucleophiles including C, N and S are comprehensively demonstrated, sequentially installing on both sides of sulfur-sulfur motif with various substituents to afford six species of unsymmetrical polysulfides including di-, tri- and even tetra-sulfides. Life-related molecules, natural products and pharmaceuticals can be successively cross-linked with sulfur-sulfur bond. Remarkably, the cyclization of tri- and tetra-peptides affords 15- and 18-membered cyclic disulfide peptides with this reagent, respectively.


Assuntos
Dissulfetos/química , Indicadores e Reagentes/química , Peptídeos/química , Sulfetos/química , Enxofre/química , Produtos Biológicos/química , Técnicas de Química Sintética/métodos , Ciclização , Indicadores e Reagentes/síntese química , Modelos Químicos , Estrutura Molecular , Oxirredução , Preparações Farmacêuticas/química
6.
Mol Cell ; 79(1): 191-198.e3, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32619469

RESUMO

We recently used CRISPRi/a-based chemical-genetic screens and cell biological, biochemical, and structural assays to determine that rigosertib, an anti-cancer agent in phase III clinical trials, kills cancer cells by destabilizing microtubules. Reddy and co-workers (Baker et al., 2020, this issue of Molecular Cell) suggest that a contaminating degradation product in commercial formulations of rigosertib is responsible for the microtubule-destabilizing activity. Here, we demonstrate that cells treated with pharmaceutical-grade rigosertib (>99.9% purity) or commercially obtained rigosertib have qualitatively indistinguishable phenotypes across multiple assays. The two formulations have indistinguishable chemical-genetic interactions with genes that modulate microtubule stability, both destabilize microtubules in cells and in vitro, and expression of a rationally designed tubulin mutant with a mutation in the rigosertib binding site (L240F TUBB) allows cells to proliferate in the presence of either formulation. Importantly, the specificity of the L240F TUBB mutant for microtubule-destabilizing agents has been confirmed independently. Thus, rigosertib kills cancer cells by destabilizing microtubules, in agreement with our original findings.


Assuntos
Antineoplásicos/farmacologia , Proliferação de Células , Glicina/análogos & derivados , Microtúbulos/efeitos dos fármacos , Neoplasias/patologia , Preparações Farmacêuticas/metabolismo , Sulfonas/farmacologia , Tubulina (Proteína)/metabolismo , Células Cultivadas , Cristalografia por Raios X , Contaminação de Medicamentos , Glicina/farmacologia , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Preparações Farmacêuticas/química , Conformação Proteica , Tubulina (Proteína)/química , Tubulina (Proteína)/genética
7.
BMC Bioinformatics ; 21(1): 322, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32689927

RESUMO

BACKGROUND: The study of DNA binding protein (DBP)-drug interactions can open a breakthrough for the treatment of genetic diseases and cancers. Currently, network-based methods are widely used for protein-drug interaction prediction, and many hidden relationships can be found through network analysis. We proposed a DCA (drug-cluster association) model for predicting DBP-drug interactions. The clusters are some similarities in the drug-binding site trimmers with their physicochemical properties. First, DBPs-drug binding sites are extracted from scPDB database. Second, each binding site is represented as a trimer which is obtained by sliding the window in the binding sites. Third, the trimers are clustered based on the physicochemical properties. Fourth, we build the network by generating the interaction matrix for representing the DCA network. Fifth, three link prediction methods are detected in the network. Finally, the common neighbor (CN) method is selected to predict drug-cluster associations in the DBP-drug network model. RESULT: This network shows that drugs tend to bind to positively charged sites and the binding process is more likely to occur inside the DBPs. The results of the link prediction indicate that the CN method has better prediction performance than the PA and JA methods. The DBP-drug network prediction model is generated by using the CN method which predicted more accurately drug-trimer interactions and DBP-drug interactions. Such as, we found that Erythromycin (ERY) can establish an interaction relationship with HTH-type transcriptional repressor, which is fitted well with silico DBP-drug prediction. CONCLUSION: The drug and protein bindings are local events. The binding of the drug-DBPs binding site represents this local binding event, which helps to understand the mechanism of DBP-drug interactions.


Assuntos
Biologia Computacional/métodos , Proteínas de Ligação a DNA/metabolismo , Bases de Dados Factuais , Interações Medicamentosas , Preparações Farmacêuticas/metabolismo , Sítios de Ligação , Simulação por Computador , Proteínas de Ligação a DNA/química , Humanos , Preparações Farmacêuticas/química , Ligação Proteica
8.
BMC Bioinformatics ; 21(1): 309, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32664863

RESUMO

BACKGROUND: Despite continued efforts using chemical similarity methods in virtual screening, currently developed approaches suffer from time-consuming multistep procedures and low success rates. We recently developed a machine learning-based chemical binding similarity model considering common structural features from molecules binding to the same, or evolutionarily related targets. The chemical binding similarity measures the resemblance of chemical compounds in terms of binding site similarity to better describe functional similarities that arise from target binding. In this study, we have shown how the chemical binding similarity could be used in virtual screening together with the conventional structure-based methods. RESULTS: The chemical binding similarity, receptor-based pharmacophore, chemical structure similarity, and molecular docking methods were evaluated to identify an effective virtual screening procedure for desired target proteins. When we tested the chemical binding similarity method with test sets of 51 kinases, it outperformed the traditional structural similarity-based methods as well as structure-based methods, such as molecular docking and receptor-based pharmacophore modeling, in terms of finding active compounds. We further validated the results by performing virtual screening (using the chemical binding similarity and receptor-based pharmacophore methods) against a completely blind dataset for mitogen-activated protein kinase kinase 1 (MEK1), ephrin type-B receptor 4 (EPHB4) and wee1-like protein kinase (WEE1). The in vitro kinase binding assay confirmed that 6 out of 13 (46.2%) for MEK1 and 2 out of 12 (16.7%) for EPHB4 were newly identified only by the chemical binding similarity model. CONCLUSIONS: We report that the virtual screening results could further be improved by combining the chemical binding similarity model with 3D-QSAR pharmacophore and molecular docking models. Not only the new inhibitors are identified in this study, but also many of the identified molecules have low structural similarity scores against already reported inhibitors and that show the revelation of novel scaffolds.


Assuntos
Simulação de Acoplamento Molecular , Relação Quantitativa Estrutura-Atividade , Área Sob a Curva , Sítios de Ligação , Humanos , Aprendizado de Máquina , Compostos Orgânicos/química , Compostos Orgânicos/metabolismo , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo , Ligação Proteica , Proteínas Quinases/química , Proteínas Quinases/metabolismo , Curva ROC
9.
Chemosphere ; 259: 127480, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32634722

RESUMO

A Na+ exchanged montmorillonite clay (Na-Mt) and its organoclay derivatives prepared with benzyldimethyltetradecylammonium (BDTA) cationic and polyoxyethylene (20)oleyl-ether (Brij-O20) non-ionic surfactants were used for first time at our knowledge as adsorbents the removal diverse pharmaceuticals (PPs) from samples collected in a rural wastewater facility (town of Josnes in France). The selected facility showed a poor efficiency for the elimination of PPs that were permanently release to the environment. Although involving different interactional mechanisms, the whole adsorbents Na-Mt, nonionic Brij-Mt and cationic BDTA-Mt organoclays, could remove the entire PPs of various chemical nature in a low concentration regime (ng L-1), where electrostatic interactions mainly controlled the adsorption. Thus, the organic PPs cations were preferentially adsorbed onto Na-Mt and Brij0.4-Mt (with its dual hydrophilic-hydrophobic nature) while anionic PPs showed a bold affinity to BDTA-Mt. The hydrophobic environment generated by the intercalation of surfactants within the interlayer space of organoclays conferred a versatility for the adsorption of numerous PPs through weak molecular forces (Van der Waals and/or pi-pi interactions). The study confirmed the proper efficiency of the studied layered materials including organoclays and emphasized about their promising interests in water remediation strategy.


Assuntos
Argila/química , Preparações Farmacêuticas/química , Eliminação de Resíduos Líquidos/métodos , Adsorção , Bentonita/química , Cátions , França , Interações Hidrofóbicas e Hidrofílicas , Tensoativos/química , Águas Residuárias/química , Água/química , Poluentes Químicos da Água/química
10.
AAPS PharmSciTech ; 21(5): 189, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651739

RESUMO

The aim of this study was to investigate the influence of the production method and the polymeric carrier on the ability to generate and maintain the supersaturation of a poorly soluble drug in biorelevant medium. The amorphous solid dispersion of sulfamethoxazole, an antibacterial drug, was produced using two different polymers by spray-drying or hot melt extrusion methods. When Eudragit EPO was used, supersaturation was maintained up to 24 h for both techniques at all drug-polymer proportions. However, when Soluplus was employed in hot melt extrusion, a smaller amount of drug was dissolved when compared to the amorphous drug. The proportion of 3:7 drug-Eudragit EPO (w/w) produced by spray-drying presented a higher amount of drug dissolved in supersaturation studies and it was able to maintain the physical stability under different storage conditions throughout the 90-day evaluation. Supersaturation generation and system stability were found to be related to more effective chemical interaction between the polymer and the drug provided by the production method, as revealed by the 1D ROESY NMR experiment. Investigation of drug-polymer interaction is critical in supersaturating drug delivery systems to avoid crystallization of the drug and to predict the effectiveness of the system. Chemical compounds studied in this article: Sulfamethoxazole (PubChem CID: 4539) and Methacrylate copolymer - Eudragit EPO (PubChem CID: 65358).


Assuntos
Preparações Farmacêuticas/química , Polietilenoglicóis/química , Ácidos Polimetacrílicos/química , Polivinil/química , Cristalização , Dessecação , Portadores de Fármacos/química , Composição de Medicamentos/métodos , Interações Medicamentosas , Estabilidade de Medicamentos , Solubilidade
11.
SAR QSAR Environ Res ; 31(6): 457-475, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32627677

RESUMO

In silico methods are often used for predicting pharmacokinetic properties of drugs due to their simplicity and cost-effectiveness. This study evaluates the penetration of 83 active pharmaceutical ingredients into human breast milk with an experimental milk-to-plasma ratio (M/P) obtained from the literature. Multiple linear regression (MLR), partial least squares (PLS) and random forest (RF) regression methods were compared to uncover the relationship between physicochemical, pharmacokinetic and membrane crossing properties of active pharmaceutical ingredients (APIs) using their rapid reference measurement value (Rf values), thin-layer chromatography (TLC) data from albumin-impregnated plates. Molecular descriptors of APIs proven to be important for their crossing into breast milk, including protein binding, ionisation state and lipophilicity and TLC data, have been included in the development of the prediction models. The best regression results were achieved by MLR (r 2 = 0.83 and r 2 = 0.86, n = 28) and RF (r 2 = 0.85, n = 58). In addition, the discriminant function analysis (DFA) was performed on acidic, basic and neutral drugs separately and showed a prediction accuracy of 93%, with M/P included as the discriminating variable.


Assuntos
Análise dos Mínimos Quadrados , Modelos Lineares , Leite Humano/química , Preparações Farmacêuticas/metabolismo , Relação Quantitativa Estrutura-Atividade , Preparações Farmacêuticas/química
12.
J Chromatogr A ; 1624: 461244, 2020 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-32540081

RESUMO

Analysis and control of stereoisomers is a major task in pharmaceutical analysis, and is a greater challenge when compounds with multiple chiral centers (MCC) are concerned. HPLC and SFC are commonly used for stereoisomer analysis in drug development, typically starting with chiral method screening. Although method screening for compounds with a single chiral center (SCC) has been well studied for 5-µm polysaccharide stationary phase particles, there are fewer reports on method screening for compounds with MCC and smaller particle sizes. In this study, we systematically evaluated the impact of key parameters in chiral method screening including column particle size (3-µm vs. sub-2 µm), nature of the chiral selector binding (coated vs. immobilized), mobile phase elution mode (isocratic vs. gradient), and separation approach (SFC vs. HPLC). A diverse set of pharmaceutical compounds with MCC and a SCC were studied. We found that the screening strategies differ between MCC and SCC compounds due to the difference in the recognition mechanism involved. Furthermore, we have developed an effective screening strategy with OD-3, AD-3 and IG-3 columns for SCC compounds which achieves larger than 90% success rate, and a combination of OD-3, AD-3, IG-3, IC-3 and AS-3 for MCC compounds which offers the best coverage.


Assuntos
Preparações Farmacêuticas/química , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia com Fluido Supercrítico , Polissacarídeos/química , Estereoisomerismo
13.
FEBS Open Bio ; 10(6): 995-1004, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-186395

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
14.
J Chromatogr A ; 1622: 461160, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32450990

RESUMO

The glutathione (GSH) trapping assay is commonly utilized for the screening and characterization of reactive metabolites produced by drug metabolism. This study describes a fluorous derivatization method for a more sensitive and selective analysis of reactive metabolites trapped by GSH using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this study, the GSH-trapped reactive metabolites, which were obtained after incubation of the test compounds with human liver microsome (HLM) in the presence of GSH and NADPH, were derivatized using the perfluoroalkylamine reagent through oxazolone chemistry. Since this reaction enabled the selective modification of the α-carboxyl group in GSH, the structural compositions of the metabolites were not affected by the derivatization. Furthermore, the selective analysis of the resulting derivatives could be performed using perfluoroalkyl-modified stationary phase LC separation via the interaction between the perfluoroalkyl-containing compounds, such as fluorous affinity, followed by detection with the precursor ion and/or enhanced product ion scan modes in MS/MS. Finally, we demonstrated the applicability of this method by analyzing perfluoroalkyl derivatives of some drug metabolites trapped by GSH in HLM incubation.


Assuntos
Cromatografia Líquida/métodos , Flúor/química , Glutationa/análise , Espectrometria de Massas em Tandem/métodos , Glutationa/química , Humanos , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismo
15.
Nat Biotechnol ; 38(9): 1087-1096, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32440005

RESUMO

Small molecules are usually compared by their chemical structure, but there is no unified analytic framework for representing and comparing their biological activity. We present the Chemical Checker (CC), which provides processed, harmonized and integrated bioactivity data on ~800,000 small molecules. The CC divides data into five levels of increasing complexity, from the chemical properties of compounds to their clinical outcomes. In between, it includes targets, off-targets, networks and cell-level information, such as omics data, growth inhibition and morphology. Bioactivity data are expressed in a vector format, extending the concept of chemical similarity to similarity between bioactivity signatures. We show how CC signatures can aid drug discovery tasks, including target identification and library characterization. We also demonstrate the discovery of compounds that reverse and mimic biological signatures of disease models and genetic perturbations in cases that could not be addressed using chemical information alone. Overall, the CC signatures facilitate the conversion of bioactivity data to a format that is readily amenable to machine learning methods.


Assuntos
Preparações Farmacêuticas/metabolismo , Bibliotecas de Moléculas Pequenas/metabolismo , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Biomarcadores Farmacológicos/metabolismo , Bases de Dados Factuais , Descoberta de Drogas , Tratamento Farmacológico , Humanos , Preparações Farmacêuticas/química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico
16.
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
17.
J Med Chem ; 63(12): 6407-6422, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32352779

RESUMO

After two decades teetering at the intersection of laboratory tool and therapeutic reality, with two siRNA drugs now clinically approved, this modality has finally come into fruition. Consistent with other emerging modalities, initial proof-of-concept efforts concentrated on coupling pharmacologic efficacy with desirable safety profiles. Consequently, thorough investigations of siRNA absorption, distribution, metabolism, and excretion (ADME) properties are lacking. Advancing ADME knowledge will aid establishment of in vitro-in vivo correlations and pharmacokinetic-pharmacodynamic relationships to optimize candidate selection through discovery and translation. Here, we outline the emerging siRNA design principles and discuss the consequences for siRNA disposition and biotransformation. We propose a conceptual framework for siRNA ADME evaluation, contextualizing the site of biotransformation product formation with PK-PD modulation, and end with a discussion around safety and regulatory considerations and future directions for this modality.


Assuntos
Biotransformação , Desenho de Fármacos , Desenvolvimento de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Preparações Farmacêuticas/química , RNA Interferente Pequeno/química , Animais , Humanos , Preparações Farmacêuticas/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacocinética , Distribuição Tecidual
18.
J Chromatogr A ; 1622: 460895, 2020 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-32408991

RESUMO

Baseline separation and analysis of multicomponent mixtures of closely related pharmaceuticals using single column selectivity can often be challenging, requiring the combination of orthogonal stationary and mobile phase methods to monitor all the species and optimize reaction outcomes. In recent years, two-dimensional liquid chromatography (2D-LC) has become a valuable tool for improving peak capacity and selectivity. Though powerful, standard 2D-LC instrumentation and software can often lead to tedious method development and has a requirement for very specific expertise that is poorly suited for a fast-paced industrial environment. In this regard, the introduction of an automated online 2D-LC setup that could screen multiple columns in both dimensions without manual intervention will undeniably serve to streamline column/mobile phase selection and secure the viability of 2D-LC as a mainstay instrument for industrial applications. Herein, we introduce and investigate a multicolumn online 2D-LC approach that simplifies column screening and method development dramatically. This setup incorporates 6-position column selection valve technology whose functionality enables us to combine multiple columns in the first and second dimensions. This strategy in conjunction with diode array detection (DAD) in both dimensions and mass spectrometry (MS) acquisition in the second dimension serves to explore different columns and mobile phases as a framework for screening targeted compounds in multicomponent mixtures without having to perform chromatographic purification. Multiple online heart cutting achiral RPLC - achiral RPLC and achiral RPLC - chiral RPLC coupled to DAD and ESI-MS methods combining several stationary phase selectivity in an automated fashion are successfully applied to the separation and analysis of complex mixtures of drug substances, where in many instances, traditional 1D-ultra-high performance liquid chromatography (UHPLC) fails or delivers sub-optimal results. This automated online multicolumn 2D-LC workflow enables rapid and efficient identification of column/eluent combinations, as well as sample analysis across multiple columns in both dimensions overnight with a single click.


Assuntos
Técnicas de Química Analítica/métodos , Cromatografia Líquida de Alta Pressão , Técnicas de Química Analítica/instrumentação , Sistemas On-Line , Preparações Farmacêuticas/química
19.
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
20.
Adv Exp Med Biol ; 1194: 203-215, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32468536

RESUMO

Antibodies are proteins that are the first line of defense in the adaptive immune response of vertebrates. Thereby, they are involved in a multitude of biochemical mechanisms and clinical manifestations with significant medical interest, such as autoimmunity, the regulation of infection, and cancer. An emerging field in antibody science that is of huge medicinal interest is the development of novel antibody-interacting drugs. Such entities are the antibody-drug conjugates (ADCs), which are a new type of targeted therapy, which consist of an antibody linked to a payload drug. Overall, the underlying principle of ADCs is the discerning delivery of a drug to a target, hoping to increase the potency of the original drug. Drugena suite is a pioneering platform that employs state-of-the-art computational biology methods in the fight against neurodegenerative diseases using ADCs. Drugena encompasses an up-to-date structural database of specialized antibodies for neurological disorders and the NCI database with over 96 million entities for the in silico development of ADCs. The pipeline of the Drugena suite has been divided into several steps and modules that are closely related with a synergistic fashion under a user-friendly graphical user interface.


Assuntos
Desenho de Fármacos , Imunoconjugados , Informática Médica , Doenças Neurodegenerativas , Animais , Anticorpos Monoclonais , Humanos , Imunoconjugados/uso terapêutico , Informática Médica/métodos , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Preparações Farmacêuticas/química
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