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1.
Elife ; 102021 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-34340747

RESUMO

The discovery of a drug requires over a decade of intensive research and financial investments - and still has a high risk of failure. To reduce this burden, we developed the NICEdrug.ch resource, which incorporates 250,000 bioactive molecules, and studied their enzymatic metabolic targets, fate, and toxicity. NICEdrug.ch includes a unique fingerprint that identifies reactive similarities between drug-drug and drug-metabolite pairs. We validated the application, scope, and performance of NICEdrug.ch over similar methods in the field on golden standard datasets describing drugs and metabolites sharing reactivity, drug toxicities, and drug targets. We use NICEdrug.ch to evaluate inhibition and toxicity by the anticancer drug 5-fluorouracil, and suggest avenues to alleviate its side effects. We propose shikimate 3-phosphate for targeting liver-stage malaria with minimal impact on the human host cell. Finally, NICEdrug.ch suggests over 1300 candidate drugs and food molecules to target COVID-19 and explains their inhibitory mechanism for further experimental screening. The NICEdrug.ch database is accessible online to systematically identify the reactivity of small molecules and druggable enzymes with practical applications in lead discovery and drug repurposing.


Assuntos
Desenho de Fármacos , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos , Preparações Farmacêuticas/metabolismo , Animais , Antimetabólitos Antineoplásicos/química , Antimetabólitos Antineoplásicos/metabolismo , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Bases de Dados de Produtos Farmacêuticos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/metabolismo , Fluoruracila/química , Fluoruracila/metabolismo , Humanos , Preparações Farmacêuticas/química , Fluxo de Trabalho
2.
Int J Mol Sci ; 22(16)2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34445680

RESUMO

Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3ß is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3ß inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3ß activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43A315T mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Glicogênio Sintase Quinase 3 beta/metabolismo , Tiadiazóis/farmacologia , Idoso , Esclerose Amiotrófica Lateral/tratamento farmacológico , Esclerose Amiotrófica Lateral/metabolismo , Animais , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Proteínas de Ligação a DNA/fisiologia , Modelos Animais de Doenças , Reposicionamento de Medicamentos , Glicogênio Sintase Quinase 3 beta/fisiologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Pessoa de Meia-Idade , Neurônios Motores/metabolismo , Preparações Farmacêuticas/metabolismo , Fosforilação , Proteínas Quinases/metabolismo , Medula Espinal/metabolismo
3.
Eur J Pharm Sci ; 166: 105965, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34375679

RESUMO

Oral drug delivery is often challenged with enzymatic degradation of drug molecules in the gastrointestinal tract and high first-pass metabolism, resulting in low bioavailability. Delivery of drug molecules via the oral cavity mucosa is considered a viable option to enhance bioavailability. One of the relatively new dosage forms for transmucosal drug delivery is the oral thin film (OTF) with mucoadhesive properties that offers several advantages over conventional dosage forms, including faster dissolution, higher patient compliance, and extended oral retention by reduced salivary washout. Mucoadhesive OTFs should have sufficient muco-adhesiveness as well as suitable mechanical properties for their best performance, thus such characterization is critical in the successful design and development of OTFs. However, there is currently no FDA or USP-recommended analytical procedure or standard available for evaluating adhesiveness and mechanical properties of mucoadhesive OTFs. Therefore, we aimed to develop a fast and reliable in vitro method capable of differentiating various OTFs in terms of their adhesive strengths using a texture analyzer. We found that an in vitro gel substrate composed of 4% w/v gellan gum and 2% w/v glycerin could be used to discriminate between the adhesive features of the tested film samples. Also, our studies show that the adhesion test parameters of 0.96 N target force, probe speed of 0.1 mm/s, holding time of 15 s, and conditioning medium volume of 200 µL while using the said substrate could successfully differentiate between the adhesion strength of the OTF samples. We further examined the film samples for their physicomechanical properties to obtain a tangible and practical range of mechanical values for pharmaceutical OTFs using the puncture test and folding endurance test. We found a breaking factor above 34.5 N/mm, elongation to puncture less than 5.55% and folding endurance of at least 50 folds can be used as a starting point when designing and manufacturing OTFs.


Assuntos
Sistemas de Liberação de Medicamentos , Preparações Farmacêuticas , Adesividade , Adesivos/metabolismo , Disponibilidade Biológica , Humanos , Mucosa Bucal/metabolismo , Preparações Farmacêuticas/metabolismo
4.
Int J Mol Sci ; 22(15)2021 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-34360907

RESUMO

The superfamily of P-loop channels includes various potassium channels, voltage-gated sodium and calcium channels, transient receptor potential channels, and ionotropic glutamate receptors. Despite huge structural and functional diversity of the channels, their pore-forming domain has a conserved folding. In the past two decades, scores of atomic-scale structures of P-loop channels with medically important drugs in the inner pore have been published. High structural diversity of these complexes complicates the comparative analysis of these structures. Here we 3D-aligned structures of drug-bound P-loop channels, compared their geometric characteristics, and analyzed the energetics of ligand-channel interactions. In the superimposed structures drugs occupy most of the sterically available space in the inner pore and subunit/repeat interfaces. Cationic groups of some drugs occupy vacant binding sites of permeant ions in the inner pore and selectivity-filter region. Various electroneutral drugs, lipids, and detergent molecules are seen in the interfaces between subunits/repeats. In many structures the drugs strongly interact with lipid and detergent molecules, but physiological relevance of such interactions is unclear. Some eukaryotic sodium and calcium channels have state-dependent or drug-induced π-bulges in the inner helices, which would be difficult to predict. The drug-induced π-bulges may represent a novel mechanism of gating modulation.


Assuntos
Domínio AAA , Canais de Cálcio/metabolismo , Microscopia Crioeletrônica/métodos , Preparações Farmacêuticas/metabolismo , Canais de Potássio/metabolismo , Receptores Ionotrópicos de Glutamato/metabolismo , Canais de Potencial de Receptor Transitório/metabolismo , Canais de Sódio Disparados por Voltagem/metabolismo , Sequência de Aminoácidos , Sítios de Ligação , Canais de Cálcio/química , Biologia Computacional/métodos , Eucariotos/metabolismo , Ligantes , Modelos Moleculares , Canais de Potássio/química , Conformação Proteica em alfa-Hélice , Receptores Ionotrópicos de Glutamato/química , Alinhamento de Sequência , Canais de Potencial de Receptor Transitório/química , Canais de Sódio Disparados por Voltagem/química
5.
Expert Opin Drug Metab Toxicol ; 17(9): 1103-1124, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34253134

RESUMO

Introduction: Physiological pH and chemical pKa are two sides of the same coin in defining the ionization of a drug in the human body. The Henderson-Hasselbalch equation and pH-partition hypothesis form the theoretical base to define the impact of pH-pKa crosstalk on drug ionization and thence its absorption, distribution, metabolism, excretion, and toxicity (ADMET).Areas covered: Human physiological pH is not constant, but a diverse, dynamic state regulated by various biological mechanisms, while the chemical pKa is generally a constant defining the acidic dissociation of the drug at various environmental pH. Works on pH-pKa crosstalk are scattered in the literature, despite its significant contributions to drug pharmacokinetics, pharmacodynamics, safety, and toxicity. In particular, its impacts on drug ADMET have not been effectively linked to the physiologically based pharmacokinetic (PBPK) modeling and simulation, a powerful tool increasingly used in model-informed drug development (MIDD).Expert opinion: Lacking a full consideration of the interactions of physiological pH and chemical pKa in a PBPK model limits scientists' capability in mechanistically describing the drug ADMET. This mini-review compiled literature knowledge on pH-pKa crosstalk and its impacts on drug ADMET, from the viewpoint of PBPK modeling, to pave the way to a systematic incorporation of pH-pKa crosstalk into PBPK modeling and simulation.


Assuntos
Desenvolvimento de Medicamentos/métodos , Modelos Biológicos , Preparações Farmacêuticas/metabolismo , Animais , Simulação por Computador , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Concentração de Íons de Hidrogênio , Farmacocinética
6.
Poult Sci ; 100(9): 101228, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34293615

RESUMO

In order to explore the mechanism of liver injury induced by florfenicol (FFC) in broilers. Sixty broilers were randomly divided into 2 groups: control group: normal drinking water and feed were given every d; FFC group: tap water containing FFC (0.15g/L) was given every d and feed was taken freely; each group was given 5 dd of continuous medication and feed was taken freely. The results showed that compared with the control group, FFC could significantly inhibit the weight gain of broilers (P < 0.05), and significantly inhibit the expression of CYP1A1 and CYP2H1 in liver tissue (P < 0.05). It was found that the expression of genes related to the effect of cytochrome P450 on the metabolism of exogenous substances, the peroxisome proliferators-activated receptors signal pathway, peroxisome pathway and glutathione metabolic pathway in the liver of broilers. The results of qPCR of UDP glucuronosyltransferase family 2A1 (UGT2A1), glutathione S-transferase-like 2 (GSTAL2), hematopoietic prostaglandin D synthase (HPGDS), glutathione S-transferase theta 1(GSTT1), isocitrate dehydrogenase (NADP(+)) 1 (IDH1), acyl-CoA oxidase 2 (ACOX2), fatty acid binding protein 1 (FABP1), adenylosuccinate lyase (ADSL), and phosphoribosyl aminoim idazolesuccino carboxamide synthase (PAICS) genes which were randomly selected from the most significant genes were consistent with those of RNA-seq. The results showed that FFC can affect the drug metabolism and lipid synthesis in the liver of broiler, thus impairing the normal function of liver and the growth and development of broiler.


Assuntos
Metabolismo dos Lipídeos , Preparações Farmacêuticas , Animais , Galinhas/genética , Perfilação da Expressão Gênica/veterinária , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Preparações Farmacêuticas/metabolismo , Proteoma/metabolismo , Tianfenicol/análogos & derivados
7.
Xenobiotica ; 51(9): 983-994, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34227923

RESUMO

Chimeric mice are immunodeficient mice in which the majority of the hepatic parenchymal cells are replaced with human hepatocytes.Following intravenous administration of 24 model compounds to control and chimeric mice, human hepatic clearance (CLh) was predicted using the single-species allometric scaling (SSS) method. Predictability of the chimeric mice was better than that of the control mice.Human CLh was predicted by the physiologically based scaling (PBS) method, wherein observed CLh in chimeric mice was first converted to intrinsic CLh (CLh,int). As the liver of chimeric mice contains remaining mouse hepatocytes, CLh,int was corrected by in vitro CLh ratios of the mouse to human hepatocytes according to their hepatocyte replacement index. Further, predicted human CLh was calculated based on an assumption that CLh,int in chimeric mice normalised for their liver weight was equal to CLh,int per liver weight in humans. Consequently, better prediction performance was observed with the use of the PBS method than the SSS method.SSS method is an empirical method, and the effects of coexisting mouse metabolism cannot be avoided. However, the PBS method with in vitro CLh correction might be a potential solution and may expand the application of chimeric mice in new drug development.


Assuntos
Preparações Farmacêuticas , Animais , Quimera , Hepatócitos , Humanos , Fígado/metabolismo , Taxa de Depuração Metabólica , Camundongos , Preparações Farmacêuticas/metabolismo
8.
Methods Mol Biol ; 2342: 339-365, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272701

RESUMO

Drug transporters are universally acknowledged as important determinants of the absorption, distribution, metabolism, and excretion of both endogenous and exogenous compounds. Altered transporter function, whether due to genetic polymorphism, DDIs, disease, or environmental factors such as dietary constituents, can result in changes in drug efficacy and/or toxicity due to changes in circulating or tissue levels of either drugs or endogenous substrates.Prediction of whether and to what extent the biological fate of a drug is influenced by drug transporters, therefore, requires in vitro test systems that can accurately predict the risk and magnitude of clinical DDIs. While these in vitro assessments appear simple in theory, practitioners recognize that there are multiple factors that can influence experimental outcomes. A better understanding of these variables, including test compound characteristics, test systems, assay formats, and experimental design, will enable clear, actionable steps and translatable outcomes that may avoid unnecessary downstream clinical engagement. This chapter will delineate the role of these variables in improving in vitro assay outcomes.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Desenho de Fármacos , Interações Medicamentosas , Humanos , Cinética , Proteínas de Membrana Transportadoras/química , Projetos de Pesquisa
9.
Methods Mol Biol ; 2342: 633-642, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272708

RESUMO

This chapter deals with practical considerations on key issues such as choosing an enzyme source, determining linear conditions, and choosing appropriate substrate and organic solvent concentrations. Practical solutions for working with limited resources and carrying out inhibition experiments are also addressed. Thus, after reading this chapter, the novice reader should have a better idea of how to design, develop, and interpret basic experiments using drug metabolism enzymes.


Assuntos
Enzimas/metabolismo , Hepatócitos/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Hepatócitos/enzimologia , Humanos , Cinética , Lisossomos/enzimologia , Projetos de Pesquisa
10.
Methods Mol Biol ; 2342: 643-652, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272709

RESUMO

Characterization of enzyme kinetics in an experiment is dependent on measurement of a change in concentration of either the substrate (loss of parent) or the product (formation of metabolite). Modern analytical techniques such as ultrahigh pressure liquid chromatography, high resolution mass spectrometry, etc. have allowed accurate characterization of minute changes in concentration. Therefore, complex kinetic data such as a sigmoidal phase at low substrate concentrations or terminal half-life in a PK curve can be evaluated by stretching the limits of analytical quantification. This chapter presents some elementary dos and don'ts and provides insight into some of the underlying principles for utilizing the best possible analytical techniques when investigating enzyme kinetics. The objective of this case study is to answer the following questions: (a) Why is it necessary to determine lower and upper limits of quantification (LLOQ and ULOQ, respectively) of a bioanalytical assay, specifically for enzyme kinetic assays? How do you utilize LLOQ and ULOQ to correctly interpret your kinetic data? (b) Why should one use a linear fit and not a quadratic fit for standard curves? (c) Is quantification of an analyte possible without a reference standard? Can one assume equal signal intensities regardless of analytical technique (MS, UV)? (d) In the absence of reference standards, can you still determine kinetic constants? (e) With the need to keep substrate depletion at less than 20% for linearity assumptions, does bioanalytical variability matter? (f) What buffer do you use for your enzyme systems? How do you choose your buffer ? Does choice of bioanalytical methods (LC, MS) dictate your choice of buffer ?


Assuntos
Enzimas/metabolismo , Preparações Farmacêuticas/metabolismo , Algoritmos , Cromatografia Líquida , Humanos , Cinética , Limite de Detecção , Farmacocinética , Padrões de Referência , Projetos de Pesquisa , Espectrometria de Massas em Tandem
11.
Methods Mol Biol ; 2342: 665-684, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272711

RESUMO

An appreciation of enzyme kinetic principles can be applied in a number of drug metabolism applications. The concept for this chapter arose from a simple discussion on selecting appropriate time points to most efficiently assess metabolite profiles in a human Phase 1a clinical study (Subheading 4). By considering enzyme kinetics, a logical approach to the issue was derived. The dialog was an important learning opportunity for the participants in the discussion, and we have endeavored to capture this experience with other questions related to determination of Km and Vmax parameters, a consideration of the value of hepatocytes vs. liver microsomes, and enzyme inhibition parameters.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Metabolômica/métodos , Preparações Farmacêuticas/administração & dosagem , Algoritmos , Ensaios Clínicos Fase I como Assunto , Cálculos da Dosagem de Medicamento , Humanos , Cinética , Microssomos Hepáticos/enzimologia , Microssomos Hepáticos/metabolismo , Preparações Farmacêuticas/metabolismo
12.
Methods Mol Biol ; 2342: 709-735, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272714

RESUMO

Assessing the interactions of a new drug candidate with transporters, either as a substrate, inhibitor, or inducer, is no simple matter. There are many clinically relevant transporters, as many as nine to be evaluated for an FDA submission and up to 11 for the EMA as of 2020. Additionally, it is likely that if a compound is a substrate or inhibitor of one transporter, it will be so for other transporters as well. There are practically no specific substrates or inhibitors, presumably because the specificities of drug transporters are so broad and overlapping, and even fewer clinically relevant probes that can be used to evaluate transporter function in humans. In the case of some transporters, it is advisable to evaluate an NCE with more than one test system and/or more than one probe substrate in order to convince oneself (and regulatory authorities) that a clinical drug interaction study is not warranted. Finally, each test system has its own unique set of advantages and disadvantages. One has to appreciate the nuances of the available tools (test systems, probe substrates, etc.) to select the most relevant tools for the study and design the optimal in vitro experiment. In this chapter, several examples are used to illustrate the successful interpretation of in vitro data for both efflux and uptake transporters. Some data presented in this chapter are unpublished at the time of the compilation of this book. It has been included in this chapter to provide a sense of the complexities in transporter kinetics to the reader.


Assuntos
Proteínas de Membrana Transportadoras/metabolismo , Preparações Farmacêuticas/metabolismo , Animais , Transporte Biológico , Células CACO-2 , Linhagem Celular , Cães , Interações Medicamentosas , Humanos , Células Madin Darby de Rim Canino , Projetos de Pesquisa
13.
Methods Mol Biol ; 2342: 737-763, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272715

RESUMO

In the first edition of this book, we presented the basics of explicitly incorporating the lipid biochemistry into a confluent cell monolayer transport model and the novel findings of this model up to 2013, including the use of global optimization to fit the elementary rate constants and the efflux active P-glycoprotein (P-gp) membrane concentrations for the transport of four P-gp substrates across MDCKII-hMDR1-NKI confluent cell monolayers. This chapter is an update on that model, which has been focused primarily on discovering how microvilli morphology regulates the efflux active P-gp and the existence of, as yet, unidentified uptake transporters of P-gp substrates in all of the commonly used P-gp expressing cell lines used in the pharmaceutical industry, thereby adding new players to DDI predictions and IVIVE. The structural mass action kinetic model uses the general mass action reactions for P-gp binding and efflux, with the membrane structural parameters for the confluent cell monolayer to predict drug transport over time. Binding of drug to P-gp occurs within the cytosolic monolayer of the apical membrane, according to (a) the molar partition coefficient of the drug to the cytosolic monolayer and (b) the association rate constant, k1 (M-1 s-1), of the drug from the basolateral or apical outer monolayers into the P-gp binding site. Release of substrate from P-gp back into the cytosolic monolayer occurs with a dissociation rate constant kr (s-1) or, much less frequently, into the apical aqueous chamber with an efflux rate constant k2 (s-1). The model fits the efflux active P-gp concentration, T(0), i.e., the P-gp whose effluxed drug actually reaches the apical aqueous chamber, as opposed to the majority of P-gp whose effluxed drug is reabsorbed back into the same or neighboring microvilli prior to reaching the apical aqueous chamber. Efflux active P-gp largely resides near the tips of the microvilli. We have shown using kinetics and structured illumination microscopy that: (a) efflux active P-gp is controlled by microvilli morphology; (b) there are apical (AT) and basolateral (BT) uptake transporters for P-gp substrates in most, if not all, P-gp expressing cell lines used in the pharmaceutical industry, which exist, but which remain unidentified; (c) the lab-to-lab variability in P-gp IC50 values observed in the P-gp IC50 initiative was due to the conflated inhibition of P-gp and the basolateral digoxin uptake transporters by all 15 P-gp substrates tested in that study; (d) even the IC50 values for P-gp inhibition alone do not obey the Cheng-Prusoff relationship; (e) the fitted elementary rate constants and the molecular dissociation constant Ki for this kinetic model are system independent; and (f) the time dependence of product formation for these confluent cell monolayers is correlated with the P-gp Vmax/Km, when defined by its fitted elementary rate constants and uptake transporter clearances, without any steady-state assumptions.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Técnicas de Cultura de Células/métodos , Preparações Farmacêuticas/metabolismo , Animais , Sítios de Ligação , Transporte Biológico , Células CACO-2 , Células Cultivadas , Citosol/metabolismo , Humanos , Cinética , Microvilosidades/metabolismo , Modelos Teóricos
14.
Methods Mol Biol ; 2342: 481-550, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34272705

RESUMO

The efficacy, safety, and tolerability of drugs are dependent on numerous factors that influence their disposition. A dose that is efficacious and safe for one individual may result in sub-therapeutic or toxic blood concentrations in others. A significant source of this variability in drug response is drug metabolism, where differences in presystemic and systemic biotransformation efficiency result in variable degrees of systemic exposure (e.g., AUC, Cmax, and/or Cmin) following administration of a fixed dose.Interindividual differences in drug biotransformation have been studied extensively. It is recognized that both intrinsic factors (e.g., genetics, age, sex, and disease states) and extrinsic factors (e.g., diet , chemical exposures from the environment, and the microbiome) play a significant role. For drug-metabolizing enzymes, genetic variation can result in the complete absence or enhanced expression of a functional enzyme. In addition, upregulation and downregulation of gene expression, in response to an altered cellular environment, can achieve the same range of metabolic function (phenotype), but often in a less predictable and time-dependent manner. Understanding the mechanistic basis for variability in drug disposition and response is essential if we are to move beyond the era of empirical, trial-and-error dose selection and into an age of personalized medicine that will improve outcomes in maintaining health and treating disease.


Assuntos
Família 4 do Citocromo P450/genética , Preparações Farmacêuticas/metabolismo , Variantes Farmacogenômicos , Biotransformação , Regulação da Expressão Gênica , Humanos , Inativação Metabólica , Medicina de Precisão
15.
Chem Biol Interact ; 345: 109574, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34228969

RESUMO

NAD(P)H: Quinone Oxidoreductase 1 (NQO1) is an antioxidant enzyme that catalyzes the two-electron reduction of several different classes of quinone-like compounds (quinones, quinone imines, nitroaromatics, and azo dyes). One-electron reduction of quinone or quinone-like metabolites is considered to generate semiquinones to initiate redox cycling that is responsible for the generation of reactive oxygen species and oxidative stress and may contribute to the initiation of adverse drug reactions and adverse health effects. On the other hand, the two-electron reduction of quinoid compounds appears important for drug activation (bioreductive activation) via chemical rearrangement or autoxidation. Two-electron reduction decreases quinone levels and opportunities for the generation of reactive species that can deplete intracellular thiol pools. Also, studies have shown that induction or depletion (knockout) of NQO1 were associated with decreased or increased susceptibilities to oxidative stress, respectively. Moreover, another member of the quinone reductase family, NRH: Quinone Oxidoreductase 2 (NQO2), has a significant functional and structural similarity with NQO1. The activity of both antioxidant enzymes, NQO1 and NQO2, becomes critically important when other detoxification pathways are exhausted. Therefore, this article summarizes the interactions of NQO1 and NQO2 with different pharmacological agents, endogenous biochemicals, and environmental contaminants that would be useful in the development of therapeutic approaches to reduce the adverse drug reactions as well as protection against quinone-induced oxidative damage. Also, future directions and areas of further study for NQO1 and NQO2 are discussed.


Assuntos
Antioxidantes/metabolismo , Poluentes Ambientais/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Preparações Farmacêuticas/metabolismo , Quinona Redutases/metabolismo , Transporte de Elétrons , Humanos , Ligação Proteica
17.
Methods Mol Biol ; 2315: 263-271, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34302681

RESUMO

Pan-assay interference compounds (PAINS) are promiscuous molecules with multiple behaviors that interfere with assay readouts. Membrane PAINS are a subset of these compounds that influence the function of membrane proteins by nonspecifically perturbing the lipid membranes that surround them. Here, we describe a computational protocol to identify potential membrane PAINS molecules by calculating the effect that a given compound has on the bilayer deformation propensity.


Assuntos
Biologia Computacional/métodos , Descoberta de Drogas/métodos , Preparações Farmacêuticas/metabolismo , Bicamadas Lipídicas/metabolismo , Proteínas de Membrana/metabolismo , Membranas/metabolismo
18.
Environ Res ; 200: 111396, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34062201

RESUMO

The knowledge about the effects of pharmaceuticals on aquatic organisms has been increasing in the last decade. However, due to the variety of compounds presents in the aquatic medium, exposure scenarios and exposed organisms, there are still many gaps in the knowledge on how mixtures of such bioactive compounds affect exposed non target organisms. The crayfish Procambarus clarkii was used to analyze the toxicity effects of mixtures of ciprofloxacin, flumequine and ibuprofen at low and high concentrations (10 and 100 µg/L) over 21 days of exposure and to assess the recovery capacity of the organism after a depuration phase following exposure during additional 7 days in clean water. The crayfish accumulated the three compounds throughout the entire exposure in the hepatopancreas. The exposure to the mixture altered the abundance of proteins associated with different cells functions such as biotransformation and detoxification processes (i.e. catalase and glutathione transferase), carbohydrate metabolism and immune responses. Additionally changes in expression of genes encoding antioxidant enzymes and in activity of the corresponding enzymes (i.e. superoxide dismutase, glutathione peroxidase and glutathione transferase) were reported. Alterations at different levels of biological organization did not run in parallel under all circumstances and can be related to changes in the redox status of the target tissue. No differences were observed between control and exposed organisms for most of selected endpoints after a week of depuration, indicating that exposure to the drug mixture did not produce permanent damage in the hepatopancreas of P. clarkii.


Assuntos
Preparações Farmacêuticas , Poluentes Químicos da Água , Animais , Astacoidea , Ciprofloxacina/metabolismo , Ciprofloxacina/toxicidade , Fluoroquinolonas , Hepatopâncreas/metabolismo , Ibuprofeno/toxicidade , Análise Multinível , Estresse Oxidativo , Preparações Farmacêuticas/metabolismo , Proteômica , Poluentes Químicos da Água/metabolismo , Poluentes Químicos da Água/toxicidade
19.
Chem Biol Interact ; 345: 109566, 2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34174250

RESUMO

Mammalian carboxylesterases (CES), the key members of the serine hydrolase superfamily, hydrolyze a wide range of endogenous substances and xenobiotics bearing ester or amide bond(s). In humans, most of identified CES are segregated into the CES1A and CES2A subfamilies. Strong inhibition on human CES (including hCES1A and hCES2A) may modulate pharmacokinetic profiles of CES-substrate drugs, thereby changing the pharmacological and toxicological responses of these drugs. This review covered recent advances in discovery of hCES inhibitors from clinically available medications, as well as their impact on CES-associated drug metabolism. Three comprehensive lists of hCES inhibitors deriving from clinically available medications including therapeutic drugs, pharmaceutical excipients and herbal medicines, alongside with their inhibition potentials and inhibition parameters, are summarized. Furthermore, the potential risks of hCES inhibitors to trigger drug/herb-drug interactions (DDIs/HDIs) and future concerns in this field are highlighted. Potent hCES inhibitors may trigger clinically relevant DDIs/HDIs, especially when these inhibitors are co-administrated with CES substrate-drugs with very narrow therapeutic windows. All data and knowledge presented here provide key information for the clinicians to assess the risks of clinically available hCES inhibitors on drug metabolism. In future, more practical and highly specific substrates for hCES1A/hCES2A should be developed and used for studies on CES-mediated DDIs/HDIs both in vitro and in vivo.


Assuntos
Carboxilesterase/antagonistas & inibidores , Carboxilesterase/metabolismo , Inibidores Enzimáticos/farmacologia , Preparações Farmacêuticas/metabolismo , Animais , Descoberta de Drogas , Humanos , Inativação Metabólica/efeitos dos fármacos
20.
J Phys Chem A ; 125(25): 5633-5642, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34142824

RESUMO

Computational approaches for predicting drug-target interactions (DTIs) play an important role in drug discovery since conventional screening experiments are time-consuming and expensive. In this study, we proposed end-to-end representation learning of a graph neural network with an attention mechanism and an attentive bidirectional long short-term memory (BiLSTM) to predict DTIs. For efficient training, we introduced a bidirectional encoder representations from transformers (BERT) pretrained method to extract substructure features from protein sequences and a local breadth-first search (BFS) to learn subgraph information from molecular graphs. Integrating both models, we developed a DTI prediction system. As a result, the proposed method achieved high performances with increases of 2.4% and 9.4% for AUC and recall, respectively, on unbalanced datasets compared with other methods. Extensive experiments showed that our model can relatively screen potential drugs for specific protein. Furthermore, visualizing the attention weights provides biological insight.


Assuntos
Biologia Computacional/métodos , Gráficos por Computador , Aprendizado Profundo , Descoberta de Drogas/métodos , Preparações Farmacêuticas/metabolismo , Proteínas/química , Proteínas/metabolismo , Sequência de Aminoácidos
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