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1.
Curr Protoc ; 2(1): e350, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35041265

RESUMO

Mapping MHC-II binding peptides derived from an antigenic protein for potential CD4+ T-cell epitopes has been challenging due to a lack of experimental approaches that are both quantitative and rapid. The rate-limiting steps in current approaches include the construction of single MHC allele expressing cell lines and/or the purification of the MHC-II allelic proteins for peptide elution (i.e., mass spectrometry) or in vitro peptide binding (i.e., ELISA) assays. These labor-intensive steps typically take up to 4 months or more. In this protocol, we describe a system that uses yeast cells to display "empty" (i.e., without covalently linked peptides) MHC-II heterodimers that are capable of binding exogenously added peptides of interest. This yeast-MHC-II system eliminates the time-consuming soluble MHC-II purification steps, allowing rapid identification of peptide ligands from protein antigens (RIPPA). The amount of peptide loading to MHC-II or the extent of competition between indicator and competitor peptides at the surface of yeast cells can be quantitatively determined using flow cytometric analysis. Importantly, the protocol only takes ∼1 month from the construction of plasmids and the yeast display of "empty" MHC-II to the quantitative determination of MHC-II binding peptides from a given antigen. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Yeast display of "empty" MHC-II Support Protocol: Construction of yeast shuttle vector expressing "empty" MHC-II Basic Protocol 2: Peptide competition on the surface of yeast cells Alternate Protocol: RIPPA in a 96-well format.


Assuntos
Antígenos de Histocompatibilidade Classe II , Saccharomyces cerevisiae , Epitopos de Linfócito T , Ligantes , Peptídeos , Saccharomyces cerevisiae/genética
2.
Medicine (Baltimore) ; 101(1): e28286, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35029877

RESUMO

ABSTRACT: This study investigates the active components and mechanism of Shufeng Jiedu Capsules (SFJDC) against novel coronavirus through network pharmacology and molecular docking.The TCMSP, TCMID, and BATMAN-TCM databases were used to retrieve the components of SFJDC. The active components were screened by ADME (absorption, distribution, metabolism, and excretion) parameters, and identified by Pubchem, Chemical Book, and ChemDraw softwares. The molecular docking ligands were constructed. SARS Coronavirus-2 Major Protease (SARS-CoV-2-Mpro) and angiotension converting enzyme 2 (ACE2) were used as molecular docking receptors. AutoDock software was used for molecular docking. Cytoscape 3.7.1 software was used to generate an herbs-active components-targets network. Gene Ontology gene function and Kyoto Encyclopedia of Genes and Genomes signal pathway analysis were performed by DAVID data.A total of 1244 components were identified from SFJDC, and 210 active components were obtained. Among them, 97 active components were used as docking ligands to dock with SARS-CoV-2-Mpro and ACE2. There were 48 components with good binding activity to SARS-CoV-2-Mpro. Ten active components (including 7-Acetoxy-2-methylisoflavone, Kaempferol, Quercetin, Baicalein, Glabrene, Glucobrassicin, Isoglycyrol, Wogonin, Petunidin, and Luteolin) combined with SARS-CoV-2-Mpro and ACE2 simultaneously. Among them, Kaempferol, Wogonin, and Baicalein showed higher binding activity. The herbs-active components-targets network contained 7 herbs, 10 active components, and 225 targets. The 225 target targets were involved in 653 biological processes of Gene Ontology analysis and 130 signal pathways (false discovery rate ≤ 0.01) of Kyoto Encyclopedia of Genes and Genomes analysis.The active components of SFJDC (such as Kaempferol, Wogonin, and Baicalein) may combine with ACE2 and act on multiple signaling pathways and targets to exert therapeutic effect on novel coronavirus.


Assuntos
COVID-19/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Simulação de Acoplamento Molecular/métodos , SARS-CoV-2/efeitos dos fármacos , Enzima de Conversão de Angiotensina 2 , Humanos , Quempferóis , Ligantes , SARS-CoV-2/genética
3.
Appl Biochem Biotechnol ; 194(1): 291-301, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34988845

RESUMO

Corona virus pandemic outbreak also known as COVID-19 has created an imbalance in this world. Scientists have adopted the use of natural or alternative medicines which are consumed mostly as dietary supplements to boost the immune system as herbal remedies. India is famous for traditional medicinal formulations which includes 'Trikadu'-a combination of three acrids, namely Zingiber officinale, Piper nigrum and Piper longum which have antioxidant properties that boost our immune system hence acting as a strong preventive measure. In this study, AutoDock 4.0 was used to study interaction between the phytocompounds of Trikadu with RNA-dependent polymerase protein and enveloped protein of the SARS-CoV-2 virus. Analysis of the results showed that coumarin, coumaperine and bisdemethoxycurcumin showed strong bonding interactions with both the proteins. We can conclude that Trikadu has the potential molecules; hence, it can be incorporated in the diet to boost the immune system as a preventive measure against the virus.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/imunologia , Fitoterapia , Preparações de Plantas/uso terapêutico , SARS-CoV-2 , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , COVID-19/virologia , Simulação por Computador , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/efeitos dos fármacos , Suplementos Nutricionais , Gengibre/química , Humanos , Sistema Imunitário/efeitos dos fármacos , Índia , Ligantes , Medicina Tradicional , Simulação de Acoplamento Molecular , Compostos Fitoquímicos/química , Compostos Fitoquímicos/uso terapêutico , Piper/química , Piper nigrum/química , Preparações de Plantas/isolamento & purificação , Plantas Medicinais/química , SARS-CoV-2/química , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/efeitos dos fármacos
4.
J Enzyme Inhib Med Chem ; 37(1): 563-572, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35012384

RESUMO

On account of its crucial role in the virus life cycle, SARS-COV-2 NSP13 helicase enzyme was exploited as a promising target to identify a novel potential inhibitor using multi-stage structure-based drug discovery approaches. Firstly, a 3D pharmacophore was generated based on the collected data from a protein-ligand interaction fingerprint (PLIF) study using key interactions between co-crystallised fragments and the NSP13 helicase active site. The ZINC database was screened through the generated 3D-pharmacophore retrieving 13 potential hits. All the retrieved hits exceeded the benchmark score of the co-crystallised fragments at the molecular docking step and the best five-hit compounds were selected for further analysis. Finally, a combination between molecular dynamics simulations and MM-PBSA based binding free energy calculations was conducted on the best hit (compound FWM-1) bound to NSP13 helicase enzyme, which identified FWM-1 as a potential potent NSP13 helicase inhibitor with binding free energy equals -328.6 ± 9.2 kcal/mol.


Assuntos
COVID-19/tratamento farmacológico , Descoberta de Drogas , Exorribonucleases/antagonistas & inibidores , Ensaios de Triagem em Larga Escala/métodos , Simulação de Acoplamento Molecular , SARS-CoV-2/efeitos dos fármacos , Proteínas não Estruturais Virais/antagonistas & inibidores , COVID-19/virologia , Domínio Catalítico , Humanos , Ligantes , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade
5.
Biosens Bioelectron ; 200: 113899, 2022 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-34974264

RESUMO

Fluorescently-labeled solute-binding proteins that alter their fluorescence output in response to ligand binding have been utilized as biosensors for a variety of applications. Coupling protein ligand binding to altered fluorescence output often requires trial and error-based testing of both multiple labeling positions and fluorophores to produce a functional biosensor with the desired properties. This approach is laborious and can lead to reduced ligand binding affinity or altered ligand specificity. Here we report the Computational Identification of Non-disruptive Conjugation sites (CINC) for streamlined identification of fluorophore conjugation sites. By exploiting the structural dynamics properties of proteins, CINC identifies positions where conjugation of a fluorophore results in a fluorescence change upon ligand binding without disrupting protein function. We show that a CINC-developed maltooligosaccharide (MOS)-detecting biosensor is capable of rapid (kon = 20 µM-1s-1), sensitive (sub-µM KD) and selective MOS detection. The MOS-detecting biosensor is modular with respect to the spectroscopic properties and demonstrates portability to detecting MOS released via α-amylase-catalyzed depolymerization of starch using both a stopped-flow and a microplate reader assay. Our MOS-detecting biosensor represents a first-in-class probe whose design was guided by changes in localized dynamics of individual amino acid positions, supporting expansion of the CINC pipeline as an indispensable tool for a wide range of protein engineering applications.


Assuntos
Técnicas Biossensoriais , Carboidratos , Corantes Fluorescentes , Ligantes , Espectrometria de Fluorescência
6.
BMC Bioinformatics ; 22(Suppl 12): 324, 2022 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-35045825

RESUMO

BACKGROUND: Alkaline earth metal ions are important protein binding ligands in human body, and it is of great significance to predict their binding residues. RESULTS: In this paper, Mg2+ and Ca2+ ligands are taken as the research objects. Based on the characteristic parameters of protein sequences, amino acids, physicochemical characteristics of amino acids and predicted structural information, deep neural network algorithm is used to predict the binding sites of proteins. By optimizing the hyper-parameters of the deep learning algorithm, the prediction results by the fivefold cross-validation are better than those of the Ionseq method. In addition, to further verify the performance of the proposed model, the undersampling data processing method is adopted, and the prediction results on independent test are better than those obtained by the support vector machine algorithm. CONCLUSIONS: An efficient method for predicting Mg2+ and Ca2+ ligand binding sites was presented.


Assuntos
Algoritmos , Redes Neurais de Computação , Sítios de Ligação , Humanos , Ligantes , Ligação Proteica
7.
ChemistryOpen ; 11(1): e202100238, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34981908

RESUMO

Bio-inorganic complexes inspired by hydrogenase enzymes are designed to catalyze the hydrogen evolution reaction (HER). A series of new diiron hydrogenase mimic complexes with one or two terminal tris(4-methoxyphenyl)phosphine and different µ-bridging dithiolate ligands and show catalytic activity towards electrochemical proton reduction in the presence of weak and strong acids. A series of propane- and benzene-dithiolato-bridged complexes was synthesized, crystallized, and characterized by various spectroscopic techniques and quantum chemical calculations. Their electrochemical properties as well as the detailed reaction mechanisms of the HER are elucidated by density functional theory (DFT) methods. The nature of the µ-bridging dithiolate is critically controlling the reaction and performance of the HER of the complexes. In contrast, terminal phosphine ligands have no significant effects on redox activities and mechanism. Mono- or di-substituted propane-dithiolate complexes afford a sequential reduction (electrochemical; E) and protonation (chemical; C) mechanism (ECEC), while the µ-benzene dithiolate complexes follow a different reaction mechanism and are more efficient HER catalysts.


Assuntos
Hidrogenase , Catálise , Hidrogênio , Ligantes , Prótons
8.
SAR QSAR Environ Res ; 33(1): 49-61, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-35048766

RESUMO

The enzyme acetylcholinesterase (AChE) is currently a therapeutic target for the treatment of neurodegenerative diseases. These diseases have highly variable causes but irreversible evolutions. Although the treatments are palliative, they help relieve symptoms and allow a better quality of life, so the search for new therapeutic alternatives is the focus of many scientists worldwide. In this study, a QSAR-SVM classification model was developed by using the MATLAB numerical computation system and the molecular descriptors implemented in the Dragon software. The obtained parameters are adequate with accuracy of 88.63% for training set, 81.13% for cross-validation experiment and 81.15% for prediction set. In addition, its application domain was determined to guarantee the reliability of the predictions. Finally, the model was used to predict AChE inhibition by a group of quinazolinones and benzothiadiazine 1,1-dioxides obtained by chemical synthesis, resulting in 14 drug candidates with in silico activity comparable to acetylcholine.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Humanos , Ligantes , Simulação de Acoplamento Molecular , Qualidade de Vida , Relação Quantitativa Estrutura-Atividade , Reprodutibilidade dos Testes
9.
Anal Chim Acta ; 1192: 339370, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35057928

RESUMO

The binding characteristics of fatty acids (FA) to human serum albumin (HSA) have been garnering increased attention due to the importance of FAs in numerous in clinical and biological fields. In this study, we investigate the binding characteristics of two long-chain FAs - linoleic acid (LA; FA 18:2, ω-6) and alpha-linoleic acid (aLA; FA 18:3, ω-3) -studying their binding isotherms to HAS using solid-phase microextraction (SPME) probes. The binding isotherms showed that ligand saturation occurred at B ≈ 7 for both ligands, which indicates that there are at least seven specific binding sites available in HSA for FAs. The most notable feature of the binding isotherm graph was the presence of only one set of specific binding sites - we ignored nonspecific binding interaction because it is not important for these ligands. A Scatchard plot was employed to understand how these binding sites interacted with each other, both positively and negatively, and the apparent affinity of these ligands was estimated by their Hill's coefficients (KaLA = 7.7 × 105 L mol-1 and KLA = 2.1 × 106 L mol-1 for aLA and LA ligands, respectively) - with similar values as those values previously published in the literature, establishing the feasibility of SPME as an appropriate technique for binding studies. The experimental data is supported by mathematical models that were developed using the experimental data and COMSOL Multiphysics software. An in-silico comparison of the SPME extraction kinetics for aLA in an HSA binding matrix confirmed the suitability of mathematical models and provided insight into the microextraction mechanism in complex samples.


Assuntos
Ácidos Graxos , Albumina Sérica Humana , Sítios de Ligação , Humanos , Ligantes
10.
Eur J Med Chem ; 227: 113906, 2022 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-34656901

RESUMO

Proteolysis targeting chimeras (PROTACs), which hijack proteins of interest (POIs) and recruit E3 ligases for target degradation via the ubiquitin-proteasome pathway, are a novel drug discovery paradigm that has been widely used as biological tools and medicinal molecules with the potential of clinical application value. To date, a wide variety of small molecule PROTACs have been developed. Importantly, VHL-based PROTACs have emerged to be a promising approach for proteins, including those non-druggable ones, such as transcriptional factors and scaffold proteins. VHL-based PRTOACs have been developed for the treatment of diseases that are difficult to be dealt with by conventional methods, such as radiotherapy, chemotherapy, and small molecule inhibitors. In this review, the recent advances of VHL-based PRTOACs were summarized, and the chances and challenges associated with this area were also highlighted.


Assuntos
Bibliotecas de Moléculas Pequenas/farmacologia , Proteína Supressora de Tumor Von Hippel-Lindau/antagonistas & inibidores , Humanos , Ligantes , Estrutura Molecular , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/química , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
11.
Methods Mol Biol ; 2385: 19-46, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34888714

RESUMO

Since the beginning of this century, target-mediated drug disposition has become a central concept in modeling drug action in drug development. It combines a range of processes, such as turnover, protein binding, internalization, and non-specific elimination, and often serves as a nucleus of more complex pharmacokinetic models. It is simple enough to comprehend but complex enough to be able to describe a wide range of phenomena and data sets. However, the complexity comes at a price: many parameters. In this chapter, we present an overview of the temporal development of the compounds involved after different types of drug doses and offer convenient handles for dissecting data sets in a sophisticated manner in order to estimate the values of these parameters, such as rate constants and pertinent concentrations.


Assuntos
Modelos Biológicos , Cinética , Ligantes , Preparações Farmacêuticas , Distribuição Tecidual
12.
Methods Mol Biol ; 2385: 161-174, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34888721

RESUMO

The advances in computational chemistry and biology, computer science, structural biology, and molecular biology go in parallel with the rapid progress in target-based systems. This technique has become a powerful tool in medicinal chemistry for the identification of hit molecules. The recent developments in target-based systems have played a major role in the creation of libraries of compounds, and it has also been widely applied for the design of molecular docking methods. The main advantage of this method is that it hits the fragment that has the strongest binding, has relatively small size, and leads to better compounds in terms of pharmacokinetic properties when compared with virtual screening (VS) and high-throughput screening (HTS) hits. De novo design is an essential aspect of target-based systems and requires the synthesis of chemical to allow the design of promising compound.


Assuntos
Desenho de Fármacos , Biologia Computacional , Ensaios de Triagem em Larga Escala , Ligantes , Simulação de Acoplamento Molecular
13.
Methods Mol Biol ; 2385: 237-253, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34888723

RESUMO

Surface plasmon resonance (SPR) is a real-time kinetic measurement principle that can probe the kinetic interactions between ligands and their binding sites, and lies at the backbone of pharmaceutical, biosensing, and biomolecular research. The extraction of dissociation rates from SPR-response signals often relies on several commonly adopted assumptions, one of which is the exponential decay of the dissociation part of the response signal. However, certain conditions, such as high density of binding sites or high concentration fluctuations near the surface as compared to the bulk, can lead to non-exponential decays via ligand rebinding or facilitated dissociation. Consequently, fitting the data with an exponential function can underestimate or overestimate the measured dissociation rates. Here, we describe a set of alternative fit functions that can take such effects into consideration along with plasmonic sensor design principles with key performance metrics, thereby suggesting methods for error-free high-precision extraction of the dissociation rates.


Assuntos
Ressonância de Plasmônio de Superfície , Benchmarking , Sítios de Ligação , Técnicas Biossensoriais , Cinética , Ligantes
14.
Methods Mol Biol ; 2385: 255-292, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34888724

RESUMO

A quantitative thermodynamic understanding of the noncovalent association of (bio)molecules is of central importance in molecular life sciences. An important quantity characterizing (bio)molecular association is the binding affinity or absolute binding free energy. In recent years, the computational prediction of absolute binding free energies has evolved considerably in terms of accuracy, computational speed, and user-friendliness. In this chapter, we first give an overview of how absolute free energies are defined and how they can be determined with computational means. We proceed with an outline of the theoretical basis of the two most reliable methods, potential of mean force, and double decoupling calculations. In particular, we describe how the sampling problem can be alleviated by application of restraints. Finally, we provide step-by-step instructions of how to set up corresponding molecular simulations with a commonly employed molecular dynamics simulation engine.


Assuntos
Entropia , Simulação de Dinâmica Molecular , Ligantes , Ligação Proteica
15.
Methods Mol Biol ; 2385: 313-323, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34888726

RESUMO

Many proteins have a solvent-exposed binding cleft, which permits their inhibitors to bind and unbind without significant protein conformation transforms. The binding/unbinding pathways of these protein-inhibitor complexes can be rather straightforwardly sampled by using umbrella sampling (US) simulation methods. During a US simulation, the Cα atoms of the protein are restrained via a harmonic force. The potential of mean force (PMF) along the binding pathway can be estimated by using the weighted histogram analysis method (WHAM). The binding affinity is then computed as the difference in PMF between the binding and unbinding states.


Assuntos
Proteínas/metabolismo , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação Proteica , Solventes , Termodinâmica
16.
Methods Mol Biol ; 2385: 325-334, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34888727

RESUMO

Simulations of ligand-protein interactions can be very useful for drug design and to gain biological insight. Full pathways of ligand-protein binding can be used to get information about ligand binding transition states, which form the rate-limiting step of the binding and release processes. However, these simulations are typically limited by the presence of large energy barriers that separate stable poses of interest. Here we describe a simulation protocol for exploring and analyzing landscapes of ligand-protein interactions that makes use of molecular docking, enhanced molecular simulation with the weighted ensemble algorithm, and network analysis. It can be accomplished using a modest cluster of graphics processing units and freely accessible software. This protocol focuses on the construction and analysis of a network model of ligand binding poses and provides links to resources that describe the other steps in more detail. The end result of this protocol is a map of the ligand-protein binding landscape that identifies transition states of the ligand binding pathway, as well as alternative bound poses that could be stabilized with modifications to the ligand.


Assuntos
Descoberta de Drogas , Sítios de Ligação , Cinética , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Proteínas
17.
Anal Chim Acta ; 1190: 339265, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34857129

RESUMO

Trinucleotide repeats (TRs) with abnormal lengths and atypical folding are implicated in various neurodegenerative diseases. The least stable cytosine-cytosine (C-C) mismatches in TRs when structuring into homoduplexes/hairpins have more chance in certain sequence contexts to preferentially adopt an extrahelical (E-motif) conformation with respect to those in polarity-inverted intrahelical counterparts. Herein, we designed a trihydroxyphenyl porphyrin ligand (POH3) to meet the challenge towards resolving the E-motif conformation. POH3 exhibited a specific 2:1 binding with DNAs adopting the E-motif cytosine conformation, independent of the TRs length. The trihydroxyl pattern was very crucial to gain the E-motif selectivity over the polarity-inverted counterparts via the complementary hydrogen bonding that occurred in the minor groove. Our work first elucidates the rationale in designing ligands to selectively resolve the E-motif nucleotides within TRs.


Assuntos
Porfirinas , DNA/genética , Ligantes , Conformação de Ácido Nucleico , Repetições de Trinucleotídeos
18.
ACS Appl Mater Interfaces ; 14(1): 191-200, 2022 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-34933561

RESUMO

At present, the most powerful new drugs for COVID-19 are antibody proteins. In addition, there are some star small molecule drugs. However, there are few studies on nanomaterials. Here, we study the intact graphene (IG), defective graphene (DG), and graphene oxide (GO) interacting with COVID-19 protein. We find that they show progressive inhibition of COVID-19 protein. By using molecular dynamics simulations, we study the interactions between SARS-CoV-2 3CL Mpro and graphene-related materials (GRMs): IG, DG, and GO. The results show that Mpro can be absorbed onto the surfaces of investigated materials. DG and GO interacted with Mpro more intensely, causing the decisive part of Mpro to become more flexible. Further analysis shows that compared to IG and GO, DG can inactivate Mpro and inhibit its expression effectively by destroying the active pocket of Mpro. Our work not only provides detailed and reliable theoretical guidance for the application of GRMs in treating with SARS-CoV-2 but also helps in developing new graphene-based anti-COVID-19 materials.


Assuntos
Proteases 3C de Coronavírus/química , Grafite/química , Simulação de Dinâmica Molecular , SARS-CoV-2/metabolismo , Adsorção , Sítios de Ligação , COVID-19/patologia , COVID-19/virologia , Domínio Catalítico , Proteases 3C de Coronavírus/metabolismo , Grafite/metabolismo , Humanos , Ligantes , SARS-CoV-2/isolamento & purificação
19.
Expert Opin Pharmacother ; 23(2): 273-283, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34928189

RESUMO

BACKGROUND: A new voltage-gated Ca2+ channel α2δ ligand, mirogabalin, was first approved for treating peripheral neuropathic pain in Japan in 2019. This is the first report on the prescription status of mirogabalin using a large-scale prescription database. RESEARCH DESIGN AND METHODS: The authors analyzed the prescription data of 12,924 patients prescribed mirogabalin between 1 June and 31 August 2020. The endpoints were the number of patients prescribed, prescription days, prescription doses, dose changes, co-prescription patterns, medication possession ratio (MPR), and treatment discontinuation rates (TDRs). RESULTS: Mirogabalin was newly prescribed to 7,914 patients in the 3-month study period. Most patients were prescribed mirogabalin at about 10 mg/day during the study period, and 30.9% of patients were prescribed ≥ 20 mg/day on Day 90 after the first prescription. The most frequently prescribed concomitant drug was celecoxib. The MPR (80 to 110%) was 86.2%, indicating good treatment adherence. The cumulative TDRs during ≤ 7 Days, Days 31-60, and 61-90 were 14.0%, 70.0%, and 77.9%, respectively. CONCLUSIONS: Mirogabalin was prescribed to a considerable number of patients. These results may be useful for optimizing mirogabalin use for patients with peripheral neuropathic pain in daily clinical practice. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000042592.


Assuntos
Compostos Bicíclicos com Pontes , Prescrições , Humanos , Japão , Ligantes
20.
Biol Chem ; 403(1): 27-41, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34505459

RESUMO

Inflammation is a central element of many neurodegenerative diseases. Formyl peptide receptors (FPRs) can trigger several receptor-dependent signal transduction pathways that play a key role in neuroinflammation and neurodegeneration. They are chemotactic receptors that help to regulate pro- and anti-inflammatory responses in most mammals. FPRs are primarily expressed in the immune and nervous systems where they interact with a complex pattern of pathogen-derived and host-endogenous molecules. Mounting evidence points towards a contribution of FPRs - via neuropathological ligands such as Amyloid beta, and neuroprotective ligands such as Humanin, Lipoxin A4, and Annexin A1 - to multiple pathological aspects of neurodegenerative diseases. In this review, we aim to summarize the interplay of FPRs with neuropathological and neuroprotective ligands. Next, we depict their capability to trigger a number of ligand-dependent cell signaling pathways and their potential to interact with additional intracellular cofactors. Moreover, we highlight first studies, demonstrating that a pharmacological inhibition of FPRs helps to ameliorate neuroinflammation, which may pave the way towards novel therapeutic strategies.


Assuntos
Doenças Neurodegenerativas , Receptores de Formil Peptídeo , Peptídeos beta-Amiloides , Animais , Humanos , Ligantes , Doenças Neurodegenerativas/tratamento farmacológico
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