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1.
Sci Total Environ ; 803: 149918, 2022 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-34482133

RESUMO

Co-sorption of metal ions and anions/ligands at the mineral-water interface plays a critical role in regulating the mobility, transport, fate, and bioavailability of these components in natural environments. This review focuses on co-sorption of metal ions and naturally occurring anions/ligands on environmentally relevant minerals. The underlying mechanisms for their interfacial reactions are summarized and the environmental impacts are discussed. Co-sorption mechanisms of these components depend on a variety of factors, such as the identity and properties of minerals, pH, species and concentration of metal ions and anions/ligands, addition sequence of co-sorbed ions, and reaction time. The simultaneous presence of metal ions and anions/ligands alters the initial sorption behaviors with promotive or competitive effects. Promotive effects are mainly attributed to surface electrostatic interactions, ternary surface complexation, and surface precipitation, especially for the co-sorption systems of metal ions and inorganic anions on minerals. Competitive effects involve potential complexation of metal-anions/ligands in solution or their competition for surface adsorption sites. Organic ligands usually increase metal ion sorption on minerals at low pH via forming ternary surface complexes or surface precipitates, but inhibit metal ion sorption via the formation of aqueous complexes at high pH. The different mechanisms may act simultaneously during metal ion and anion/ligand co-sorption on minerals. Finally, the potential application for remediation of metal-contaminated sites is discussed based on the different co-sorption behaviors. Future challenges and topics are raised for metal-anion/ligand co-sorption research.


Assuntos
Metais , Minerais , Adsorção , Ânions , Concentração de Íons de Hidrogênio , Íons , Ligantes
2.
Chemosphere ; 286(Pt 2): 131726, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34343921

RESUMO

Metal-organic frameworks (MOFs) have been investigated recently as effective visible light photocatalysts. In this report, we synthesized nickel, iron, and titanium-based MOFs with different oxidation states of metal ions and aminoterephthalic acid ligand for photocatalytic degradation of Rhodamine B (RhB) dye under solar light irradiation. The photoluminescence analysis revealed that the Fe-MOF could suppress the recombination of photoinduced charges and effectively degrade the dye. The photocatalytic experiment demonstrated that the Fe-MOF exhibited higher degradation efficiency of dye (90 %) compared to the Ni-MOF (9 %) and Ti-MOF (50 %) at pH 7 in 90 min. In addition, the effects of catalyst amount, dye concentration, and solution pH on dye degradation were investigated. The photodegradation of dye using Fe-MOF was well-fitted to the first-order kinetics with an R2 value of 0.9987. Furthermore, reactive oxygen species test and electron paramagnetic resonance study revealed that the superoxide anion radicals were mainly responsible for the dye degradation. Cyclic test analysis indicates that there was no substantial decrease in the degradation efficiency of dye after four consecutive cycles.


Assuntos
Estruturas Metalorgânicas , Catálise , Ligantes , Luz , Rodaminas
3.
Methods Mol Biol ; 2390: 301-319, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34731475

RESUMO

Ultrahigh-throughput virtual screening (uHTVS) is an emerging field linking together classical docking techniques with high-throughput AI methods. We outline mechanistic docking models' goals and successes. We present different AI accelerated workflows for uHTVS, mainly through surrogate docking models. We showcase a novel feature representation technique, molecular depictions (images), as a surrogate model for docking. Along with a discussion on analyzing screens using regression enrichment surfaces at the tens of billion scale, we outline a future for uHTVS screening pipelines with deep learning.


Assuntos
Aprendizado Profundo , Ligantes , Simulação de Acoplamento Molecular , Proteínas
4.
Methods Mol Biol ; 2390: 383-407, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34731478

RESUMO

The discovery and development of drugs is a long and expensive process with a high attrition rate. Computational drug discovery contributes to ligand discovery and optimization, by using models that describe the properties of ligands and their interactions with biological targets. In recent years, artificial intelligence (AI) has made remarkable modeling progress, driven by new algorithms and by the increase in computing power and storage capacities, which allow the processing of large amounts of data in a short time. This review provides the current state of the art of AI methods applied to drug discovery, with a focus on structure- and ligand-based virtual screening, library design and high-throughput analysis, drug repurposing and drug sensitivity, de novo design, chemical reactions and synthetic accessibility, ADMET, and quantum mechanics.


Assuntos
Inteligência Artificial , Aprendizado Profundo , Desenho de Fármacos , Ligantes , Aprendizado de Máquina
5.
Chemosphere ; 287(Pt 2): 132193, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34826906

RESUMO

In order to remove and recover uranium from acidic uranium-bearing wastewater in uranium mining and metallurgy. Herein, a novel chitosan/Chlorella pyrenoidosa composite adsorbent bearing phosphate ligand (CSP/CP) was designed and synthesized, demonstrating a high uranium adsorption capacity at a pH of 5 and excellent selectivity in an aqueous solution with eight coexisting ions. The CSP/CP exhibits a maximum adsorption capacity (1393.338 mg g-1) and selectivity (Su = 80.53%) for uranium, which is higher than many reported adsorbents. Mechanism analysis shows that the surface of CSP/CP is rich in hydroxyl, amino, phosphate and carboxyl groups, resulting in an excellent three-dimensional structure with active sites for high-performance uranium adsorption; U(VI) is selectively bound via ion exchanges with -COOH and -OH and through surface complexation with NH2 and PO. Furthermore, by desorption with 0.1 M Na2CO3 + 2% H2O2 at 318 K, CSP/CP can be recycled more than five times. It provides a new scientific basis for the preparation of high selectivity composite adsorbent by chitosan.


Assuntos
Quitosana , Chlorella , Urânio , Adsorção , Peróxido de Hidrogênio , Cinética , Ligantes , Fosfatos
6.
Methods Mol Biol ; 2390: 191-205, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34731470

RESUMO

Drug-target residence time, the duration of binding at a given protein target, has been shown in some protein families to be more significant for conferring efficacy than binding affinity. To carry out efficient optimization of residence time in drug discovery, machine learning models that can predict that value need to be developed. One of the main challenges with predicting residence time is the paucity of data. This chapter outlines all of the currently available ligand kinetic data, providing a repository that contains the largest publicly available source of GPCR-ligand kinetic data to date. To help decipher the features of kinetic data that might be beneficial to include in computational models for the prediction of residence time, the experimental evidence for properties that influence residence time are summarized. Finally, two different workflows for predicting residence time with machine learning are outlined. The first is a single-target model trained on ligand features; the second is a multi-target model trained on features generated from molecular dynamics simulations.


Assuntos
Aprendizado de Máquina , Humanos , Cinética , Ligantes , Ligação Proteica , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais
7.
Methods Mol Biol ; 2390: 273-299, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34731474

RESUMO

In the latest years, the application of deep generative models to suggest virtual compounds is becoming a new and powerful tool in drug discovery projects. The idea behind this review is to offer an updated view on de novo design approaches based on artificial intelligent (AI) algorithms, with a particular focus on ligand-based methods. We start this review by reporting a brief overview of the most relevant de novo design approaches developed before the use of AI techniques. We then describe the nowadays most common neural network architectures employed in ligand-based de novo design, together with an up-to-date list of more than 100 deep generative models found in the literature (2017-2020). In order to show how deep generative approaches are applied into drug discovery context, we report all the now available studies in which generated compounds have been synthetized and their biological activity tested. Finally, we discuss what we envisage as beneficial future directions for further application of deep generative models in de novo drug design.


Assuntos
Aprendizado Profundo , Desenho de Fármacos , Inteligência Artificial , Ligantes , Redes Neurais de Computação
8.
Handb Exp Pharmacol ; 271: 65-82, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33387066

RESUMO

The kappa opioid receptor (KOR) has emerged as a promising therapeutic target for pain and itch treatment. There is growing interest in biased agonists that preferentially activate select signaling pathways downstream of KOR activation on the cellular level due to their therapeutic promise in retaining the analgesic and antipruritic effects and eliminating the sedative and dysphoric effects of KOR signaling on the physiological level. The concept of ligand-selective signaling includes that biased ligands promote KOR to selectively recruit one transducer or regulator protein over another, introducing bias into the signaling cascade at the very receptor-proximal level. Measuring agonist effects directly at the receptor has remained challenging and previous studies have focused on inferring agonist-selective KOR engagement with G protein relative to ß-arrestin based on downstream signaling readouts. Here we discuss novel strategies to directly assess ligand-selective effects on receptor activation using KOR-interacting biosensors. The conformation-specific cytoplasmic biosensors are disconnected from the endogenous signaling machinery and provide a direct receptor-proxy readout of ligand effects in living cells. Receptor-biosensor interaction is ligand concentration dependent and can be used to determine relative ligand potency and efficacy. In addition, the biosensors reveal the existence of two dimensions of agonist bias in the cellular context: Firstly, agonists can selectively produce discrete protein-engaged KOR states and secondly, agonists can differ in the precise subcellular location at which they activate KOR. We discuss the value and the limitations of using orthogonal receptor-interacting biosensors in the quest to understand functional selectivity amongst KOR agonists in the cellular context.


Assuntos
Técnicas Biossensoriais , Receptores Opioides kappa , Proteínas de Ligação ao GTP/metabolismo , Ligantes , beta-Arrestinas
9.
Handb Exp Pharmacol ; 271: 163-195, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33454858

RESUMO

The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.


Assuntos
Analgésicos Opioides , Receptores Opioides kappa , Analgésicos Opioides/farmacologia , Dinorfinas , Humanos , Ligantes , Relação Estrutura-Atividade
10.
Handb Exp Pharmacol ; 271: 547-577, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34363128

RESUMO

Kappa opioid receptor (KOR) neuroimaging using positron emission tomography (PET) has been immensely successful in all phases of discovery and validation in relation to radiotracer development from preclinical imaging to human imaging. There are now several KOR-specific PET radiotracers that can be utilized for neuroimaging, including agonist and antagonist ligands, as well as C-11 and F-18 variants. These technologies will increase KOR PET utilization by imaging centers around the world and have provided a foundation for future studies. In this chapter, I review the advances in KOR radiotracer discovery, focusing on ligands that have been translated into human imaging, and highlight key attributes unique to each KOR PET radiotracer. The utilization of these radiotracers in KOR PET neuroimaging can be subdivided into three major investigational classes: the first, measurement of KOR density; the second, measurement of KOR drug occupancy; the third, detecting changes in endogenous dynorphin following activation or deactivation. Given the involvement of the KOR/dynorphin system in a number of brain disorders including, but not limited to, pain, itch, mood disorders and addiction, measuring KOR density in the living brain will offer insight into the chronic effects of these disorders on KOR tone in humans. Notably, KOR PET has been successful at measuring drug occupancy in the human brain to guide dose selection for maximal therapeutic efficacy while avoiding harmful side effects. Lastly, we discuss the potential of KOR PET to detect changes in endogenous dynorphin in the human brain, to elucidate neural mechanisms and offer critical insight into disease-modifying therapeutics. We conclude with comments on other translational neuroimaging modalities such as MRI that could be used to study KOR-dynorphin tone in the living human brain.


Assuntos
Tomografia por Emissão de Pósitrons , Receptores Opioides kappa , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Dinorfinas , Humanos , Ligantes
11.
Handb Exp Pharmacol ; 271: 197-220, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34463847

RESUMO

Ligands for kappa opioid receptors (KOR) have potential uses as non-addictive analgesics and for the treatment of pruritus, mood disorders, and substance abuse. These areas continue to have major unmet medical needs. Significant advances have been made in recent years in the preclinical development of novel opioid peptides, notably ones with structural features that inherently impart stability to proteases. Following a brief discussion of the potential therapeutic applications of KOR agonists and antagonists, this review focuses on two series of novel opioid peptides, all-D-amino acid tetrapeptides as peripherally selective KOR agonists for the treatment of pain and pruritus without centrally mediated side effects, and macrocyclic tetrapeptides based on CJ-15,208 that can exhibit different opioid profiles with potential applications such as analgesics and treatments for substance abuse.


Assuntos
Antagonistas de Entorpecentes , Receptores Opioides kappa , Animais , Desenvolvimento de Medicamentos , Humanos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL
12.
Handb Exp Pharmacol ; 271: 41-64, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33945028

RESUMO

The structure of the human kappa opioid receptor (KOR) in complex with the long-acting antagonist JDTic was solved crystallographically in 2012 and, along with structures of other opioid receptors, revolutionized our understanding of opioid system function and pharmacology. More recently, active state KOR structure was also determined, giving important insights into activation mechanisms of the receptor. In this review, we will discuss how the understanding of atomistic structures of KOR established a key platform for deciphering details of subtype and functional selectivity of KOR-targeting ligands and for discovery of new chemical probes with potentially beneficial pharmacological profiles.


Assuntos
Descoberta de Drogas , Receptores Opioides kappa , Analgésicos Opioides/farmacologia , Humanos , Ligantes , Receptores Opioides
13.
J Colloid Interface Sci ; 607(Pt 2): 1373-1381, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34583042

RESUMO

The ability to control the properties of monolayer protected gold nanoparticles (MPNPs) discloses unrevealed features stemming from collective properties of the ligands forming the monolayer and presents opportunities to design new materials. To date, the influence of ligand end-group size and capacity to form hydrogen bonds on structure and hydration of small MPNPs (<5 nm) has been poorly studied. Here, we show that both features determine ligands order, solvent accessibility, capacity to host hydrophobic compounds and interfacial properties of MPNPs. The polarity perceived by a radical probe and its binding constant with the monolayer investigated by electron spin resonance is rationalized by molecular dynamics simulations, which suggest that larger space-filling groups - trimethylammonium, zwitterionic and short polyethylene glycol - favor a radial organization of the thiolates, whereas smaller groups - as sulfonate - promote the formation of bundles. Zwitterionic ligands create a surface network of hydrogen bonds, which affects nanoparticle hydrophobicity and maximize the partition equilibrium constant of the probe. This study discloses the role of the chemistry of the end-group on monolayer features with effects that span from molecular- to nano-scale and opens the door to a shift in the conception of new MPNPs exploiting the end-group as a novel design motif.


Assuntos
Ouro , Nanopartículas Metálicas , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Simulação de Dinâmica Molecular
14.
J Colloid Interface Sci ; 607(Pt 2): 1762-1775, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34600340

RESUMO

Excess fluoride in water poses a threat to ecology and human health, which has attracted global attention. In this study, a series of lanthanum-based metal-organic frameworks (La-MOFs) were synthesized by varying the organic ligands (i.e., terephthalic acid (BDC), trimesic acid (BTC), biphenyl-4,4-dicarboxylic acid (BPDC), 2,5-dihydroxyterephthalic acid (BHTA), and 1,2,4,5-benzenetetracarboxylic acid (PMA)) to control the microscopic structure of the MOFs and subsequently apply them for the removal of fluoride in water. The maximum capture capacities of La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC at 298 K are 105.2, 125.9, 145.5, 158.9, and 171.7 mg g-1, respectively. The adsorption capacity is greater than most reported adsorbents. The adsorption isotherms of La-MOFs for fluoride are well fit to the Langmuir isotherm model. In addition, the adsorption kinetics of La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC follows the pseudo-second-order kinetic model, and the kinetic rate-limiting step of adsorption is chemical adsorption. Thermodynamics revealed that temperature is favorable for the adsorption of fluoride. Meanwhile, La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC are suitable for the removal of fluoride in a relatively wide pH range (4.0-9.0). Simultaneously, from X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) analysis, electrostatic attraction and ligand exchange are identified as the main action mechanisms for the adsorption of fluoride of La-MOFs. The prepared La-MOFs are used as efficient adsorbents for removal of fluoride in actual water, indicating that they have great potential in removing fluoride in real and complex environmental water. This work provides a new strategy for designing adsorbents with adjustable microstructure and expected function to effectively recover fluorosis in water.


Assuntos
Estruturas Metalorgânicas , Poluentes Químicos da Água , Adsorção , Fluoretos , Humanos , Concentração de Íons de Hidrogênio , Cinética , Lantânio , Ligantes , Espectroscopia de Infravermelho com Transformada de Fourier , Água , Poluentes Químicos da Água/análise
15.
Chemosphere ; 286(Pt 3): 131930, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34426290

RESUMO

A toxicokinetic-toxicodynamic model was constructed to delineate the exposure-response causality. The model could be used: to predict metal accumulation considering the influence of water chemistry and biotic ligand characteristics; to simulate the dynamics of subcellular partitioning considering metabolism, detoxification, and elimination; and to predict chronic toxicity as represented by biomarker responses from the concentration of metals in the fraction of potentially toxic metal. The model was calibrated with data generated from an experiment in which the Zebra mussel Dreissena polymorpha was exposed to Cu at nominal concentrations of 25 and 50 µg/L and with varied Na+ concentrations in water up to 4.0 mmol/L for 24 days. Data used in the calibration included physicochemical conditions of the exposure environment, Cu concentrations in subcellular fractions, and oxidative stress-induced responses, i.e. glutathione-S-transferase activity and lipid peroxidation. The model explained the dynamics of subcellular Cu partitioning and the effect mechanism reasonably well. With a low affinity constant for Na + binding to Cu2+ uptake sites, Na + had limited influence on Cu2+ uptake at low Na+ concentrations in water. Copper was taken up into the metabolically available pool (MAP) at a largely higher rate than into the cellular debris. Similar Cu concentrations were found in these two fractions at low exposure levels, which could be attributed to sequestration pathways (metabolism, detoxification, and elimination) in the MAP. However, such sequestration was inefficient as shown by similar Cu concentrations in detoxified fractions with increasing exposure level accompanied by the increasing Cu concentration in the MAP.


Assuntos
Dreissena , Poluentes Químicos da Água , Animais , Cobre/toxicidade , Ligantes , Metais , Poluentes Químicos da Água/toxicidade
16.
Int J Mol Sci ; 22(21)2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34769170

RESUMO

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has received global attention due to the serious threat it poses to public health. Since the outbreak in December 2019, millions of people have been affected and its rapid global spread has led to an upsurge in the search for treatment. To discover hit compounds that can be used alone or in combination with repositioned drugs, we first analyzed the pharmacokinetic and toxicological properties of natural products from Brazil's semiarid region. After, we analyzed the site prediction and druggability of the SARS-CoV-2 main protease (Mpro), followed by docking and molecular dynamics simulation. The best SARS-CoV-2 Mpro complexes revealed that other sites were accessed, confirming that our approach could be employed as a suitable starting protocol for ligand prioritization, reinforcing the importance of catalytic cysteine-histidine residues and providing new structural data that could increase the antiviral development mainly against SARS-CoV-2. Here, we selected 10 molecules that could be in vitro assayed in response to COVID-19. Two compounds (b01 and b02) suggest a better potential for interaction with SARS-CoV-2 Mpro and could be further studied.


Assuntos
Produtos Biológicos/farmacologia , COVID-19/tratamento farmacológico , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/efeitos dos fármacos , Desenho de Fármacos , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , Antivirais/química , Antivirais/farmacologia , Sítios de Ligação , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Conformação Proteica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/efeitos dos fármacos
17.
J Chromatogr A ; 1659: 462648, 2021 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-34739963

RESUMO

A hydrophilic metal-organic network based on Ti4+ and dual natural ligand, tannic acid (TA) and phytic acid (PA), has been developed to enrich phosphopeptides from complex bio-samples prior to liquid chromatography-mass spectrometric analysis. Due to the strong chelation ability of TA and PA, abundant Ti4+ can be immobilized in the material, forming hydrophilic network by one-step coordination-driven self-assembly approach. The sorbent, TA-Ti-PA@Fe3O4, exhibited satisfactory selectivity for the phosphopeptides in the tryptic digest of ß-casein, and can eliminate the interference components in 1000-fold excess of bovine serum albumin. The adsorption capacity of the sorbents for phosphopeptides was up to 35.2 mg g-1 and the adsorbing equilibrium can be reached in 5 min. The adsorbing mechanism has been investigated and the results indicated that the Ti4+ in forms of [Ti(f-TA)(H2O)4]2+, [Ti(f-PA)(H2O)4]2+ and Ti(f-PA)2(H2O)2 may play an important role in the adsorption process. The sorbent of the TA-Ti-PA@Fe3O4 has been applied to enrichment of the phosphopeptides in tryptic digest of rat liver lysate, and 3408 phosphopeptides have been identified, while the numbers of the identified phosphopeptides were 2730 and 1217 when the sample was enriched by the commercial TiO2 and Fe3+-IMAC kit, respectively. This work provides a strategy to enrich phosphopeptides from complex samples and shows great potential application in phosphoproteome research.


Assuntos
Fosfopeptídeos , Titânio , Animais , Cromatografia de Afinidade , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Ratos
18.
Molecules ; 26(21)2021 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-34771075

RESUMO

Uracil-DNA glycosylases are enzymes that excise uracil bases appearing in DNA as a result of cytosine deamination or accidental dUMP incorporation from the dUTP pool. The activity of Family 1 uracil-DNA glycosylase (UNG) activity limits the efficiency of antimetabolite drugs and is essential for virulence in some bacterial and viral infections. Thus, UNG is regarded as a promising target for antitumor, antiviral, antibacterial, and antiprotozoal drugs. Most UNG inhibitors presently developed are based on the uracil base linked to various substituents, yet new pharmacophores are wanted to target a wide range of UNGs. We have conducted virtual screening of a 1,027,767-ligand library and biochemically screened the best hits for the inhibitory activity against human and vaccinia virus UNG enzymes. Although even the best inhibitors had IC50 ≥ 100 µM, they were highly enriched in a common fragment, tetrahydro-2,4,6-trioxopyrimidinylidene (PyO3). In silico, PyO3 preferably docked into the enzyme's active site, and in kinetic experiments, the inhibition was better consistent with the competitive mechanism. The toxicity of two best inhibitors for human cells was independent of the presence of methotrexate, which is consistent with the hypothesis that dUMP in genomic DNA is less toxic for the cell than strand breaks arising from the massive removal of uracil. We conclude that PyO3 may be a novel pharmacophore with the potential for development into UNG-targeting agents.


Assuntos
Inibidores Enzimáticos/farmacologia , Pirimidinas/farmacologia , Uracila-DNA Glicosidase/antagonistas & inibidores , Vírus Vaccinia/enzimologia , Inibidores Enzimáticos/química , Humanos , Cinética , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/química , Uracila-DNA Glicosidase/metabolismo
19.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(9): 1032-1039, 2021 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-34839857

RESUMO

OBJECTIVE: To study the effect of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) regulating dendritic cells (DC) on the immune status of sepsis, and analyze the effect of PD-1/PD-L1 on prognosis. METHODS: Twenty-five patients with sepsis in the intensive care unit (ICU) of the Affiliated Hospital of Zunyi Medical University from October 2018 to September 2019 were collected and followed up for 28 days. According to the 28-day survival of patients, patients were divided into survival group and death group. Among them, 10 cases were in the survival group and 15 cases were in the death group. Simultaneously, 20 healthy subjects in our hospital during the same period served as the healthy control group. Peripheral blood of patients with sepsis was taken within 24 hours after diagnosis, and the healthy control group was taken at the time of enrollment. Flow cytometry was used to detect the proportion of CD4+T and CD8+T cells, the ratio of T cell subsets (CD4/CD8), the expression of PD-1 on CD4+T and CD8+T cells, and the expression of PD-L1 and CD86 in DC. Enzyme linked immunosorbent assay (ELISA) was used to detect the levels of interleukin-10 (IL-10) and tumor necrosis factor-α (TNF-α) in serum. Spearman correlation analysis was used to analyze the correlation between CD11c+PD-L1 and CD4+PD-1, CD8+PD-1, TNF-α, DC, CD11c+CD86, T cell subpopulation ratio, CD4+T cells, CD8+T cells, and IL-10. Binary Logistic regression was used to analyze the risk factors affecting the death of patients with sepsis, and receiver operator characteristic curve (ROC curve) was drawn to evaluate the predictive value of independent risk factors on the prognosis of patients. RESULTS: The scores of acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) in the death group were higher than that in the survival group (APACHE II score: 27.0±7.3 vs. 17.0±3.9, SOFA score: 15.1±4.1 vs. 10.7±2.7, both P < 0.05). The ratio of T cell subsets in the survival group and the death group was less than 1, the death group was lower than that in the survival group (CD4/CD8: 0.54±0.15 vs. 0.79±0.09, P < 0.05), and the ratio of T cell subsets in the healthy control group was greater than 1. Compared with healthy control group, the levels of CD4+T cells, CD8+T cells, CD11c+DC, CD11c+CD86, IL-10 and TNF-α in survival group and death group were significantly decreased, the level of CD4+PD-1,CD8+PD-1, CD11c+PD-L1 were significantly increased,and the changes in the above indicators in the death group were significant compared with the survival group [CD4+T cells: 0.14±0.07 vs. 0.22±0.08, CD8+T cells: 0.24±0.07 vs. 0.28±0.10, CD11c+DC: 0.84±0.14 vs. 0.93±0.03, CD11c+CD86: (58.83±20.77)% vs. (78.24±9.39)%, IL-10 (ng/L): 34.22±13.98 vs. 18.49±5.55, TNF-α (ng/L): 95.30±29.33 vs. 67.00±20.16, CD4+PD-1: (39.58±10.08)% vs. (27.03±6.35)%, CD8+PD-1: (38.77±11.91)% vs. (29.15±8.37)%, CD11c+PD-L1: (21.13±11.54)% vs. (12.11±8.34)%, all P < 0.05]. Spearman correlation analysis showed that CD11c+PD-L1 was positively correlated with CD4+PD-1, CD8+PD-1, and IL-10 (r values were 0.748, 0.713, 0.898, all P < 0.05), while was negatively correlated with DC, CD11c+CD86, T cell subpopulation ratio, CD4+T cells, CD8+T cells, and TNF-α (r values were -0.587, -0.906, -0.840, -0.706, -0.513, -0.820, all P < 0.05). Multivariate binary Logistic regression analysis showed that CD4+T PD-1 was an independent risk factor for the prognosis of sepsis patients [odds ratio (OR) = 1.463, 95% confidence interval (95%CI) = 1.032-2.074, P = 0.033]. ROC curve analysis showed that CD4+T PD-1 had certain predictive value for the prognosis of patients with sepsis [area under ROC curve (AUC) = 0.857, 95%CI was 0.709-1.000, P < 0.01). When the best predictive value was 34.48%, the sensitivity, specificity, and accuracy were 66.7%, 90.0%, and 85.7% respectively. CONCLUSIONS: Up-regulation of PD-1/PD-L1 in peripheral blood could inhibit the activation and proliferation of DC, affect the activation of T cells, and induce immunosuppressive state. PD-1/PD-L1 can reflect the immune status of patients with sepsis. The expression of PD-1 on CD4+T cells may have important significance for the evaluation of prognosis.


Assuntos
Antígeno B7-H1 , Sepse , Apoptose , Células Dendríticas , Humanos , Imunidade , Ligantes , Prognóstico , Curva ROC , Estudos Retrospectivos
20.
BMC Bioinformatics ; 22(1): 542, 2021 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-34749664

RESUMO

BACKGROUND: Accurate prediction of protein-ligand binding affinity is important for lowering the overall cost of drug discovery in structure-based drug design. For accurate predictions, many classical scoring functions and machine learning-based methods have been developed. However, these techniques tend to have limitations, mainly resulting from a lack of sufficient energy terms to describe the complex interactions between proteins and ligands. Recent deep-learning techniques can potentially solve this problem. However, the search for more efficient and appropriate deep-learning architectures and methods to represent protein-ligand complex is ongoing. RESULTS: In this study, we proposed a deep-neural network model to improve the prediction accuracy of protein-ligand complex binding affinity. The proposed model has two important features, descriptor embeddings with information on the local structures of a protein-ligand complex and an attention mechanism to highlight important descriptors for binding affinity prediction. The proposed model performed better than existing binding affinity prediction models on most benchmark datasets. CONCLUSIONS: We confirmed that an attention mechanism can capture the binding sites in a protein-ligand complex to improve prediction performance. Our code is available at https://github.com/Blue1993/BAPA .


Assuntos
Aprendizado de Máquina , Proteínas , Sítios de Ligação , Ligantes , Ligação Proteica , Proteínas/metabolismo
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