RESUMO
Human infection with the coronavirus disease 2019 (COVID-19) is mediated by the binding of the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the human angiotensin-converting enzyme 2 (ACE2). The frequent mutations in the receptor-binding domain (RBD) of the spike protein induced the emergence of variants with increased contagion and can hinder vaccine efficiency. Hence, it is crucial to better understand the binding mechanisms of variant RBDs to human ACE2 and develop efficient methods to characterize this interaction. In this work, we present an approach that uses machine learning to analyze the molecular dynamics simulations of RBD variant trajectories bound to ACE2. Along with the binding free energy calculation, this method was used to characterize the major differences in ACE2-binding capacity of three SARS-CoV-2 RBD variants-namely the original Wuhan strain, Omicron BA.1, and the more recent Omicron BA.5 sublineages. Our analyses assessed the differences in binding free energy and shed light on how it affects the infectious rates of different variants. Furthermore, this approach successfully characterized key binding interactions and could be deployed as an efficient tool to predict different binding inhibitors to pave the way for new preventive and therapeutic strategies.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , Aprendizado de Máquina , Simulação de Dinâmica Molecular , Ligação Proteica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/química , Humanos , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/genética , COVID-19/virologia , COVID-19/metabolismo , Sítios de Ligação , Mutação , Domínios e Motivos de Interação entre ProteínasRESUMO
Down syndrome is the most common chromosomal abnormality in humans. Patients with Down syndrome have hematologic disorders, including mild to moderate thrombocytopenia. In case of Down syndrome, thrombocytopenia is not associated with bleeding, and it remains poorly characterized regarding molecular mechanisms. We investigated the effects of overexpression of Dyrk1A, an important factor contributing to some major Down syndrome phenotypes, on platelet number and bleeding in mice. Mice overexpressing Dyrk1A have a decrease in platelet number by 20%. However, bleeding time was found to be reduced by 50%. The thrombocytopenia and the decreased bleeding time observed were not associated to an abnormal platelet receptors expression, to a defect of platelet activation by ADP, thrombin or convulxin, to the presence of activated platelets in the circulation or to an abnormal half-life of the platelets. To propose molecular mechanisms explaining this discrepancy, we performed a network analysis of Dyrk1A interactome and demonstrated that Dyrk1A, fibronectin and fibrinogen interact indirectly through two distinct clusters of proteins. Moreover, in mice overexpressing Dyrk1A, increased plasma fibronectin and fibrinogen levels were found, linked to an increase of the hepatic fibrinogen production. Our results indicate that overexpression of Dyrk1A in mice induces decreased bleeding consistent with increased plasma fibronectin and fibrinogen levels, revealing a new role of Dyrk1A depending on its indirect interaction with these two proteins.
Assuntos
Síndrome de Down , Trombocitopenia , Animais , Humanos , Camundongos , Plaquetas/metabolismo , Síndrome de Down/metabolismo , Fibrinogênio/metabolismo , Fibronectinas/metabolismo , Hemorragia/metabolismo , Trombocitopenia/metabolismo , Quinases DyrkRESUMO
Insulin-degrading enzyme (IDE) is a ubiquitously expressed metallopeptidase that degrades insulin and a large panel of amyloidogenic peptides. IDE is thought to be a potential therapeutic target for type-2 diabetes and neurodegenerative diseases, such as Alzheimer's disease. IDE catalytic chamber, known as a crypt, is formed, so that peptides can be enclosed and degraded. However, the molecular mechanism of the IDE function and peptide recognition, as well as its conformation changes, remains elusive. Our study elucidates IDE structural changes and explains how IDE conformational dynamics is important to modulate the catalytic cycle of IDE. In this aim, a free-substrate IDE crystallographic structure (PDB ID: 2JG4) was used to model a complete structure of IDE. IDE stability and flexibility were studied through molecular dynamics (MD) simulations to witness IDE conformational dynamics switching from a closed to an open state. The description of IDE structural changes was achieved by analysis of the cavity and its expansion over time. Moreover, the quasi-harmonic analysis of the hinge connecting IDE domains and the angles formed over the simulations gave more insights into IDE shifts. Overall, our results could guide toward the use of different approaches to study IDE with different substrates and inhibitors, while taking into account the conformational states resolved in our study.
Assuntos
Insulisina/química , Simulação de Dinâmica Molecular , Humanos , Ligação de Hidrogênio , Termodinâmica , Água/químicaRESUMO
The large number of proteins found in the human body implies that a drug may interact with many proteins, called off-target proteins, besides its intended target. The PatchSearch web server provides an automated workflow that allows users to identify structurally conserved binding sites at the protein surfaces in a set of user-supplied protein structures. Thus, this web server may help to detect potential off-target protein. It takes as input a protein complexed with a ligand and identifies within user-defined or predefined collections of protein structures, those having a binding site compatible with this ligand in terms of geometry and physicochemical properties. It is based on a non-sequential local alignment of the patch over the entire protein surface. Then the PatchSearch web server proposes a ligand binding mode for the potential off-target, as well as an estimated affinity calculated by the Vinardo scoring function. This novel tool is able to efficiently detects potential interactions of ligands with distant off-target proteins. Furthermore, by facilitating the discovery of unexpected off-targets, PatchSearch could contribute to the repurposing of existing drugs. The server is freely available at http://bioserv.rpbs.univ-paris-diderot.fr/services/PatchSearch.
Assuntos
Drogas em Investigação/química , Proteínas/química , Bibliotecas de Moléculas Pequenas/química , Software , Sequência de Aminoácidos , Animais , Bactérias/química , Sítios de Ligação , Bases de Dados de Compostos Químicos , Conjuntos de Dados como Assunto , Descoberta de Drogas , Drogas em Investigação/farmacologia , Humanos , Internet , Ligantes , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas/agonistas , Proteínas/antagonistas & inibidores , Proteínas/metabolismo , Alinhamento de Sequência , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
Epigallocatechin gallate (EGCG) is an inhibitor of DYRK1A, a serine/threonine kinase considered to be a major contributor of cognitive dysfunctions in Down syndrome (DS). Two clinical trials in adult patients with DS have shown the safety and efficacy to improve cognitive phenotypes using commercial green tea extract containing EGCG (45% content). In the present study, we performed a preclinical study using FontUp®, a new nutritional supplement with a chocolate taste specifically formulated for the nutritional needs of patients with DS and enriched with a standardized amount of EGCG in young mice overexpressing Dyrk1A (TgBACDyrk1A). This preparation is differential with previous one used, because its green tea extract has been purified to up 94% EGCG of total catechins. We analyzed the in vitro effect of green tea catechins not only for EGCG, but for others residually contained in FontUp®, on DYRK1A kinase activity. Like EGCG, epicatechin gallate was a noncompetitive inhibitor against ATP, molecular docking computations confirming these results. Oral FontUp® normalized brain and plasma biomarkers deregulated in TgBACDyrk1A, without negative effect on liver and cardiac functions. We compared the bioavailability of EGCG in plasma and brain of mice and have demonstrated that EGCG had well crossed the blood-brain barrier.
Assuntos
Encéfalo/efeitos dos fármacos , Catequina/análogos & derivados , Síndrome de Down/dietoterapia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Tirosina Quinases/antagonistas & inibidores , Chá/química , Animais , Antioxidantes/administração & dosagem , Antioxidantes/uso terapêutico , Disponibilidade Biológica , Biomarcadores/sangue , Biomarcadores/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/ultraestrutura , Catequina/administração & dosagem , Catequina/efeitos adversos , Catequina/química , Catequina/uso terapêutico , Suplementos Nutricionais , Síndrome de Down/sangue , Síndrome de Down/enzimologia , Síndrome de Down/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica de Varredura , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Polifenóis/análise , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/química , Proteínas Tirosina Quinases/genética , Proteínas Tirosina Quinases/metabolismo , Regulação para Cima , Quinases DyrkRESUMO
We computed the network of channels of the 3A4 isoform of the cytochrome P450 (CYP) on the basis of 16 crystal structures extracted from the Protein Data Bank (PDB). The calculations were performed with version 2 of the CCCPP software that we developed for this research project. We identified the minimal cost paths (MCPs) output by CCCPP as probable ways to access to the buried active site. The algorithm of calculation of the MCPs is presented in this paper, with its original method of visualization of the channels. We found that these MCPs constitute four major channels in CYP3A4. Among the many channels proposed by Cojocaru et al. in 2007, we found that only four of them open in 3A4. We provide a refined description of these channels together with associated quantitative data.
Assuntos
Citocromo P-450 CYP3A/química , Algoritmos , Sítios de Ligação , Domínio Catalítico , Simulação por Computador , Cristalografia por Raios X , Humanos , Domínios Proteicos , Estrutura Quaternária de Proteína , SoftwareRESUMO
Many therapeutic molecules are known to bind several proteins, which can be different from the initially targeted one. Such unexpected interactions with proteins called off-targets can lead to adverse effects. Potential off-target identification is important to predict to avoid drug side effects or to discover new targets for existing drugs. We propose a new program named PatchSearch that implements local nonsequential searching for similar binding sites on protein surfaces with a controlled amount of flexibility. It is based on detection of quasi-cliques in product graphs representing all the possible matchings between two compared structures. This method has been benchmarked on a large diversity of ligands and on five data sets ranging from 12 to more than 7000 protein structures. The experiments conducted in this study show that the PatchSearch method could be useful in the early identification of off-targets. The program and the benchmarks presented in this paper are available as an R package at https://github.com/MTiPatchSearch .
Assuntos
Biologia Computacional/métodos , Desenho de Fármacos , Modelos Moleculares , Terapia de Alvo Molecular , Conformação Proteica , Fatores de TempoRESUMO
MOTIVATION: Cytochrome P450 (CYP) is a superfamily of enzymes responsible for the metabolism of drugs, xenobiotics and endogenous compounds. CYP2D6 metabolizes about 30% of drugs and predicting potential CYP2D6 inhibition is important in early-stage drug discovery. RESULTS: We developed an original in silico approach for the prediction of CYP2D6 inhibition combining the knowledge of the protein structure and its dynamic behavior in response to the binding of various ligands and machine learning modeling. This approach includes structural information for CYP2D6 based on the available crystal structures and molecular dynamic simulations (MD) that we performed to take into account conformational changes of the binding site. We performed modeling using three learning algorithms--support vector machine, RandomForest and NaiveBayesian--and we constructed combined models based on topological information of known CYP2D6 inhibitors and predicted binding energies computed by docking on both X-ray and MD protein conformations. In addition, we identified three MD-derived structures that are capable all together to better discriminate inhibitors and non-inhibitors compared with individual CYP2D6 conformations, thus ensuring complementary ligand profiles. Inhibition models based on classical molecular descriptors and predicted binding energies were able to predict CYP2D6 inhibition with an accuracy of 78% on the training set and 75% on the external validation set.
Assuntos
Inibidores do Citocromo P-450 CYP2D6/química , Citocromo P-450 CYP2D6/química , Simulação de Dinâmica Molecular , Algoritmos , Sítios de Ligação , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2D6/farmacologia , Sistema Enzimático do Citocromo P-450/metabolismo , Humanos , Ligantes , Aprendizado de Máquina , Conformação ProteicaRESUMO
The development of chemically designed matrix metalloprotease (MMP) inhibitors has advanced the understanding of the roles of MMPs in different diseases. Most MMP probes designed are fluorogenic substrates, often suffering from photo- and chemical instability and providing a fluorescence signal of moderate intensity, which is difficult to detect and analyze when dealing with crude biological samples. Here, an inhibitor that inhibits MMP-2 more selectively than Galardin has been synthesized and used for enzyme labeling and detection of the MMP-2 activity. A complete MMP-2 recognition complex consisting of a biotinylated MMP inhibitor tagged with the streptavidin-quantum dot (QD) conjugate has been prepared. This recognition complex, which is characterized by a narrow fluorescence emission spectrum, long fluorescence lifetime, and negligible photobleaching, has been demonstrated to specifically detect MMP-2 in in vitro sandwich-type biochemical assays with sensitivities orders of magnitude higher than those of the existing gold standards employing organic dyes. The approach developed can be used for specific in vitro visualization and testing of MMP-2 in cells and tissues with sensitivities significantly exceeding those of the best existing fluorogenic techniques.
Assuntos
Metaloproteinase 2 da Matriz/efeitos dos fármacos , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pontos Quânticos , Desenho de FármacosRESUMO
Peptide-protein interactions are important to many processes of life, particularly for signal transmission or regulatory mechanisms. When no information is known about the interaction between a protein and a peptide, it is of interest to propose candidate sites of interaction at the protein surface, to assist the design of biological experiments to probe the interaction, or to serve as a starting point for more focused in silico approaches. PEP-SiteFinder is a tool that will, given the structure of a protein and the sequence of a peptide, identify protein residues predicted to be at peptide-protein interface. PEP-SiteFinder relies on the 3D de novo generation of peptide conformations given its sequence. These conformations then undergo a fast blind rigid docking on the complete protein surface, and we have found, as the result of a benchmark over 41 complexes, that the best poses overlap to some extent the experimental patch of interaction for close to 90% complexes. In addition, PEP-SiteFinder also returns a propensity index we have found informative about the confidence of the prediction. The PEP-SiteFinder web server is available at http://bioserv.rpbs.univ-paris-diderot.fr/PEP-SiteFinder.
Assuntos
Simulação de Acoplamento Molecular/métodos , Peptídeos/química , Peptídeos/metabolismo , Proteínas/química , Proteínas/metabolismo , Software , Sítios de Ligação , DNA Helicases/química , DNA Helicases/metabolismo , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Internet , Conformação ProteicaAssuntos
Depsipeptídeos/química , Inibidores de Histona Desacetilases/química , Hidrazinas/química , Depsipeptídeos/síntese química , Desenho de Fármacos , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 1/química , Desacetilase 6 de Histona/antagonistas & inibidores , Desacetilase 6 de Histona/química , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/química , Humanos , Hidrazinas/síntese química , Simulação de Acoplamento MolecularRESUMO
SARS-CoV-2 strains have made an appearance across the globe, causing over 757 million cases and over 6.85 million deaths at the time of writing. The emergence of these variants shows the amplitude of genetic variation to which the wild-type strains have been subjected. The rise of the different SARS-CoV-2 variants resulting from such genetic modification has significantly affected COVD-19's major impact on proliferation, virulence, and clinics. With the emergence of the variants of concern, the spike protein has been identified as a possible therapeutic target due to its critical role in binding to human cells and pathogenesis. These mutations could be linked to functional heterogeneity and use a different infection strategy. For example, the Omicron variant's multiple mutations should be carefully examined, as they represent one of the most widely spread strains and hint to us that there may be more genetic changes in the virus. As a result, we applied a common protocol where we reconstructed SARS-CoV-2 variants of concern and performed molecular dynamics simulations to study the stability of the ACE2-RBD complex in each variant. We also carried out free energy calculations to compare the binding and biophysical properties of the different SARS-CoV-2 variants when they interact with ACE2. Therefore, we were able to obtain consistent results and uncover new crucial residues that were essential for preserving a balance between maintaining a high affinity for ACE2 and the capacity to evade RBD-targeted antibodies. Our detailed structural analysis showed that SARS-CoV-2 variants of concern show a higher affinity for ACE2 compared to the Wuhan strain. Additionally, residues K417N and E484K/A might play a crucial role in antibody evasion, whereas Q498R and N501Y are specifically mutated to strengthen RBD affinity to ACE2 and, thereby, increase the viral effect of the COVID-19 virus.
Assuntos
Enzima de Conversão de Angiotensina 2 , COVID-19 , SARS-CoV-2 , Humanos , Enzima de Conversão de Angiotensina 2/genética , Anticorpos , COVID-19/virologia , Mutação , Ligação Proteica , SARS-CoV-2/genéticaRESUMO
Plant-derived polyphenols flavonoids are increasingly being recognized for their medicinal potential. These bioactive compounds derived from plants are gaining more interest in ameliorating adverse health risks because of their low toxicity and few side effects. Among them, therapeutic approaches demonstrated the efficacy of catechins, a major group of flavonoids, in reverting several aspects of Down syndrome, the most common genomic disorder that causes intellectual disability. Down syndrome is characterized by increased incidence of developing Alzheimer's disease, obesity, and subsequent metabolic disorders. In this focused review, we examine the main effects of catechins on comorbidities linked with Down syndrome. We also provide evidence of catechin effects on DYRK1A, a dosage-sensitive gene encoding a protein kinase involved in brain defects and metabolic disease associated with Down syndrome.
Assuntos
Catequina , Síndrome de Down , Catequina/farmacologia , Catequina/uso terapêutico , Comorbidade , Suplementos Nutricionais , Humanos , PolifenóisRESUMO
Protein tyrosine phosphatase 1B (PTP1B) is a critical regulator of different signalling cascades such as the EGFR pathway. The biological importance of PTP1B is further evidenced by knockout mice studies and the identification of recurrent mutations/deletions in PTP1B linked to metabolic and oncogenic alterations. Cisplatin is among the most widely used anticancer drug. The biological effects of cisplatin are thought to arise primarily from DNA damaging events involving cisplatin-DNA adducts. However, increasing evidence indicate that the biological properties of cisplatin could also rely on the perturbation of other processes such as cell signalling through direct interaction with certain cysteine residues in proteins. Here, we provide molecular, cellular and in vivo evidence suggesting that PTP1B is a target of cisplatin. Mechanistic studies indicate that cisplatin inhibited PTP1B in an irreversible manner and binds covalently to the catalytic cysteine residue of the enzyme. Accordingly, experiments conducted in cells and mice exposed to cisplatin showed inhibition of endogenous PTP1B and concomitant increase in tyrosine phosphorylation of EGFR. These findings are consistent with previous studies showing tyrosine phosphorylation-dependent activation of the EGFR pathway by cisplatin and with recent studies suggesting PTP1B inhibition by cisplatin and other platinum complexes. Importantly, our work provides novel mechanistic evidence that PTP1B is a protein target of cisplatin and is inhibited by this drug at molecular, cellular and in vivo levels. In addition, our work may contribute to the understanding of the pathways undergoing modulation upon cisplatin administration beyond of the established genotoxic effect of cisplatin.
Assuntos
Cisteína , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Animais , Domínio Catalítico , Cisplatino/farmacologia , Cisteína/metabolismo , Receptores ErbB/metabolismo , Camundongos , Camundongos Knockout , Fosforilação , Tirosina/metabolismoRESUMO
The recent breakthrough in the field of protein structure prediction shows the relevance of using knowledge-based based scoring functions in combination with a low-resolution 3D representation of protein macromolecules. The choice of not using all atoms is barely supported by any data in the literature, and is mostly motivated by empirical and practical reasons, such as the computational cost of assessing the numerous folds of the protein conformational space. Here, we present a comprehensive study, carried on a large and balanced benchmark of predicted protein structures, to see how different types of structural representations rank in either accuracy or calculation speed, and which ones offer the best compromise between these two criteria. We tested ten representations, including low-resolution, high-resolution, and coarse-grained approaches. We also investigated the generalization of the findings to other formalisms than the widely-used "potential of mean force" (PMF) method. Thus, we observed that representing protein structures by their ß carbons-combined or not with Cα-provides the best speed-accuracy trade-off, when using a "total information gain" scoring function. For statistical PMFs, using MARTINI backbone and side-chains beads is the best option. Finally, we also demonstrated the necessity of training the reference state on all atom types, and of including the Cα atoms of glycine residues, in a Cß-based representation.
RESUMO
In silico assessment of protein receptor interactions with small ligands is now part of the standard pipeline for drug discovery, and numerous tools and protocols have been developed for this purpose. With the SeamDock web server, we propose a new approach to facilitate access to small molecule docking for nonspecialists, including students. The SeamDock online service integrates different docking tools in a common framework that allows ligand global and/or local docking and a hierarchical approach combining the two for easy interaction site identification. This service does not require advanced computer knowledge, and it works without the installation of any programs with the exception of a common web browser. The use of the Seamless framework linking the RPBS calculation server to the user's browser allows the user to navigate smoothly and interactively on the SeamDock web page. A major effort has been put into the 3D visualization of ligand, receptor, and docking poses and their interactions with the receptor. The advanced visualization features combined with the seamless library allow a user to share with an unlimited number of collaborators, a docking session, and its full visualization states. As a result, SeamDock can be seen as a free, simple, didactic, evolving online docking resource best suited for education and training.
RESUMO
For three decades now, knowledge-based scoring functions that operate through the "potential of mean force" (PMF) approach have continuously proven useful for studying protein structures. Although these statistical potentials are not to be confused with their physics-based counterparts of the same name-i.e. PMFs obtained by molecular dynamics simulations-their particular success in assessing the native-like character of protein structure predictions has lead authors to consider the computed scores as approximations of the free energy. However, this physical justification is a matter of controversy since the beginning. Alternative interpretations based on Bayes' theorem have been proposed, but the misleading formalism that invokes the inverse Boltzmann law remains recurrent in the literature. In this article, we present a conceptually new method for ranking protein structure models by quality, which is (i) independent of any physics-based explanation and (ii) relevant to statistics and to a general definition of information gain. The theoretical development described in this study provides new insights into how statistical PMFs work, in comparison with our approach. To prove the concept, we have built interatomic distance-dependent scoring functions, based on the former and new equations, and compared their performance on an independent benchmark of 60,000 protein structures. The results demonstrate that our new formalism outperforms statistical PMFs in evaluating the quality of protein structural decoys. Therefore, this original type of score offers a possibility to improve the success of statistical PMFs in the various fields of structural biology where they are applied. The open-source code is available for download at https://gitlab.rpbs.univ-paris-diderot.fr/src/ig-score.
RESUMO
Hypoxia is an established factor of neurodegeneration. Nowadays, attention is directed at understanding how alterations in the expression of stress-related signaling proteins contribute to age dependent neuronal vulnerability to injury. The purpose of this study was to investigate how Hif-1alpha, a major neuroprotective factor, and JNK signaling, a key pathway in neurodegeneration, relate to hypoxic injury in young (6DIV) and adult (12DIV) neurons. We could show that in young neurons as compared to mature ones, the protective factor Hif-1alpha is more induced while the stress protein phospho-JNK displays lower basal levels. Indeed, changes in the expression levels of these proteins correlated with increased vulnerability of adult neurons to hypoxic injury. Furthermore, we describe for the first time that treatment with the D-JNKI1, a JNK-inhibiting peptide, rescues adult hypoxic neurons from death and contributes to Hif-1alpha upregulation, probably via a direct interaction with the Hif-1alpha protein.
Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Neurônios/enzimologia , Neurônios/patologia , Envelhecimento/patologia , Sequência de Aminoácidos , Animais , Morte Celular , Hipóxia Celular , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/química , Sistema de Sinalização das MAP Quinases , Dados de Sequência Molecular , Ligação Proteica , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , RatosRESUMO
Hydrazide derivatives of Ilomastat, carrying either aryl groups or distinct alkyl and arylsulfonyl moieties were synthesized and evaluated for their MMP inhibitory activity. Potent and selective MMP-9 inhibition (IC(50)=3 nM) was observed for compound 3m (arylsulfonyl group: 4-(4-Br-C6H4)-C6H4-SO(2)-). Interaction with the S2 enzyme subsite is mainly responsible for the inhibitory properties of this derivative as confirmed by molecular docking computation.
Assuntos
Benzeno/farmacologia , Hidrazinas/farmacologia , Indóis/farmacologia , Inibidores de Metaloproteinases de Matriz , Inibidores de Proteases/farmacologia , Ácidos Sulfônicos/farmacologia , Algoritmos , Benzeno/química , Hidrazinas/síntese química , Ácidos Hidroxâmicos , Indóis/síntese química , Concentração Inibidora 50 , Modelos Moleculares , Inibidores de Proteases/síntese química , Relação Estrutura-Atividade , Ácidos Sulfônicos/químicaRESUMO
Alcohol use disorder (AUD) represents a serious public health issue, and discovery of new therapies is a pressing necessity. Alcohol exposure has been widely demonstrated to modulate epigenetic mechanisms, such as histone acetylation/deacetylation balance, in part via histone deacetylase (HDAC) inhibition. Epigenetic factors have been suggested to play a key role in AUD. To date, 18 different mammalian HDAC isoforms have been identified, and these have been divided into four classes. Since recent studies have suggested that both epigenetic mechanisms underlying AUD and the efficacy of HDAC inhibitors (HDACIs) in different animal models of AUD may involve class I HDACs, we herein report the development of class I HDACIs, including information regarding their structure, potency, and selectivity. More effort is required to improve the selectivity, pharmacokinetics, and toxicity profiles of HDACIs to achieve a better understanding of their efficacy in reducing addictive behavior.