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Fluorescence array technologies have attracted great interest in the sensing field because of their high sensitivity, low cost, and capability of multitarget detection. However, traditional array sensing relies on multiple independent sensors and thus often requires time-consuming and laborious measurement processes. Herein, we introduce a novel fluorescence array strategy of the array-on-a-metal-organic framework (MOF), which integrates multiple array elements into a single MOF matrix to achieve facile sensing and discrimination of multiple target analytes. As a proof-of-concept system, we constructed a luminescent MOF containing three different emitting channels, including a lanthanide ion (europium/Eu3+, red emission), a fluorescent dye (7-hydroxycoumarin-4-acetic acid/HCAA, blue emission), and the MOF itself (UiO-66-type MOF, blue-violet emission). Five structurally similar nitroaromatic compounds (NACs) were chosen as the targets. All three channels of the array-on-a-MOF displayed rapid and stable fluorescence quenching responses to NACs (response equilibrium achieved within 30 s). Different responses were generated for each channel against each NAC due to the various quenching mechanisms, including photoinduced electron transfer, energy competition, and the inner filter effect. Using linear discriminant analysis, the array-on-a-MOF successfully distinguished the five NACs and their mixtures at varying concentrations and demonstrated good sensitivity to quantify individual NACs (detect limit below the advisory concentration in drinking water). Moreover, the array also showed feasibility in the sensing and discrimination of multiple NACs in real water samples. The proposed "array-on-a-MOF" strategy simplifies multitarget discrimination procedures and holds great promise for various sensing applications.
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Reaction-based de novo design refers to the in-silico generation of novel chemical structures by combining reagents using structural transformations derived from known reactions. The driver for using reaction-based transformations is to increase the likelihood of the designed molecules being synthetically accessible. We have previously described a reaction-based de novo design method based on reaction vectors which are transformation rules that are encoded automatically from reaction databases. A limitation of reaction vectors is that they account for structural changes that occur at the core of a reaction only, and they do not consider the presence of competing functionalities that can compromise the reaction outcome. Here, we present the development of a Reaction Class Recommender to enhance the reaction vector framework. The recommender is intended to be used as a filter on the reaction vectors that are applied during de novo design to reduce the combinatorial explosion of in-silico molecules produced while limiting the generated structures to those which are most likely to be synthesisable. The recommender has been validated using an external data set extracted from the recent medicinal chemistry literature and in two simulated de novo design experiments. Results suggest that the use of the recommender drastically reduces the number of solutions explored by the algorithm while preserving the chance of finding relevant solutions and increasing the global synthetic accessibility of the designed molecules.
Assuntos
Desenho de Fármacos , Algoritmos , Técnicas de Química Sintética/métodos , Técnicas de Química Sintética/estatística & dados numéricos , Química Farmacêutica/métodos , Química Farmacêutica/estatística & dados numéricos , Simulação por Computador , Desenho Assistido por Computador , Bases de Dados de Compostos Químicos , Bases de Dados de Produtos Farmacêuticos , Humanos , Aprendizado de Máquina , Bibliotecas de Moléculas PequenasRESUMO
Reaction classification has often been considered an important task for many different applications, and has traditionally been accomplished using hand-coded rule-based approaches. However, the availability of large collections of reactions enables data-driven approaches to be developed. We present the development and validation of a 336-class machine learning-based classification model integrated within a Conformal Prediction (CP) framework to associate reaction class predictions with confidence estimations. We also propose a data-driven approach for "dynamic" reaction fingerprinting to maximize the effectiveness of reaction encoding, as well as developing a novel reaction classification system that organizes labels into four hierarchical levels (SHREC: Sheffield Hierarchical REaction Classification). We show that the performance of the CP augmented model can be improved by defining confidence thresholds to detect predictions that are less likely to be false. For example, the external validation of the model reports 95% of predictions as correct by filtering out less than 15% of the uncertain classifications. The application of the model is demonstrated by classifying two reaction data sets: one extracted from an industrial ELN and the other from the medicinal chemistry literature. We show how confidence estimations and class compositions across different levels of information can be used to gain immediate insights on the nature of reaction collections and hidden relationships between reaction classes.
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Química Farmacêutica , Bases de Dados de Compostos Químicos , Aprendizado de Máquina , Modelos Químicos , Estrutura MolecularRESUMO
ß-Aminobutyric acid (BABA) induces broad-spectrum disease resistance, but also represses plant growth, which has limited its exploitation in crop protection. BABA perception relies on binding to the aspartyl-tRNA synthetase (AspRS) IBI1, which primes the enzyme for secondary defense activity. This study aimed to identify structural BABA analogues that induce resistance without stunting plant growth. Using site-directed mutagenesis, we demonstrate that the (l)-aspartic acid-binding domain of IBI1 is critical for BABA perception. Based on interaction models of this domain, we screened a small library of structural BABA analogues for growth repression and induced resistance against biotrophic Hyaloperonospora arabidopsidis (Hpa). A range of resistance-inducing compounds were identified, of which (R)-ß-homoserine (RBH) was the most effective. Surprisingly, RBH acted through different pathways than BABA. RBH-induced resistance (RBH-IR) against Hpa functioned independently of salicylic acid, partially relied on camalexin, and was associated with augmented cell wall defense. RBH-IR against necrotrophic Plectosphaerella cucumerina acted via priming of ethylene and jasmonic acid defenses. RBH-IR was also effective in tomato against Botrytis cinerea. Metabolic profiling revealed that RBH, unlike BABA, does not majorly affect plant metabolism. RBH primes distinct defense pathways against biotrophic and necrotrophic pathogens without stunting plant growth, signifying strong potential for exploitation in crop protection.
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Arabidopsis/crescimento & desenvolvimento , Arabidopsis/imunologia , Desenvolvimento Vegetal , Imunidade Vegetal , Aminobutiratos/farmacologia , Arabidopsis/metabolismo , Arabidopsis/microbiologia , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/metabolismo , Simulação por Computador , Resistência à Doença/efeitos dos fármacos , Etilenos/metabolismo , Fungos/fisiologia , Homosserina/farmacologia , Indóis/metabolismo , Solanum lycopersicum/efeitos dos fármacos , Solanum lycopersicum/crescimento & desenvolvimento , Solanum lycopersicum/microbiologia , Mutação/genética , Desenvolvimento Vegetal/efeitos dos fármacos , Doenças das Plantas/imunologia , Doenças das Plantas/microbiologia , Imunidade Vegetal/efeitos dos fármacos , Domínios Proteicos , Ácido Salicílico/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tiazóis/metabolismoRESUMO
Dissolved black carbon (DBC) is an important component of the dissolved organic matter (DOM) pool. Nonetheless, little is known about its role in the photochemical processes of organic contaminants. This study investigated the effect of DBC on the phototransformation of 17ß-estradiol in aqueous solutions under simulated sunlight. Four well-studied dissolved humic substances (DHS) were included as comparisons. DBC acted as a very effective sensitizer to facilitate the phototransformation of 17ß-estradiol. The apparent quantum yield for 17ß-estradiol phototransformation mediated by DBC was approximately six times higher than that by DHS at the same carbon concentration. Quenching experiments suggested that direct reaction with triplet-excited state DBC (3DBC*) was the predominant pathway of 17ß-estradiol phototransformation. The higher mediation efficiency of DBC than DHS is likely due to the higher contents of aromatic groups and smaller molecular sizes, which facilitated the generation of 3DBC*. The apparent quantum yield of triplet-excited states production for DBC was 4-8 times higher than that for DHS. The results suggest that 3DBC* may have a considerable contribution to the overall photoreactivity of triplet-excited state DOM in aquatic systems. Our findings also imply that DBC can play an important role in the phototransformation of organic contaminants in the environments.
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Fuligem , Poluentes Químicos da Água , Carbono , Estradiol , Substâncias Húmicas , Processos Fotoquímicos , Fotólise , Luz SolarRESUMO
Specific chemicals can prime the plant immune system for augmented defense. ß-aminobutyric acid (BABA) is a priming agent that provides broad-spectrum disease protection. However, BABA also suppresses plant growth when applied in high doses, which has hampered its application as a crop defense activator. Here we describe a mutant of Arabidopsis thaliana that is impaired in BABA-induced disease immunity (ibi1) but is hypersensitive to BABA-induced growth repression. IBI1 encodes an aspartyl-tRNA synthetase. Enantiomer-specific binding of the R enantiomer of BABA to IBI1 primed the protein for noncanonical defense signaling in the cytoplasm after pathogen attack. This priming was associated with aspartic acid accumulation and tRNA-induced phosphorylation of translation initiation factor eIF2α. However, mutation of eIF2α-phosphorylating GCN2 kinase did not affect BABA-induced immunity but relieved BABA-induced growth repression. Hence, BABA-activated IBI1 controls plant immunity and growth via separate pathways. Our results open new opportunities to separate broad-spectrum disease resistance from the associated costs on plant growth.
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Aminobutiratos/farmacologia , Arabidopsis/efeitos dos fármacos , Aspartato-tRNA Ligase/genética , Aspartato-tRNA Ligase/metabolismo , Aminobutiratos/química , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/crescimento & desenvolvimento , Genes de Plantas , Mutação , Doenças das Plantas/imunologia , Doenças das Plantas/prevenção & controle , Imunidade Vegetal/efeitos dos fármacos , Imunidade Vegetal/genética , EstereoisomerismoRESUMO
Multicomponent synthesis of 3-aminoimidazo[1,2-a]pyrimidines usually affords a product mixture containing varying amounts of the corresponding 2-amino regioisomer. Modified methods, particularly microwave heating, have been employed to suppress formation of this side-product, but none of the revised protocols are readily amenable to scale. A continuous flow adaptation was found to offer improved regioselectivity toward the targeted 3-amino regioisomer with significantly shorter reaction times and also widened the scope of the reaction to permit the use of aliphatic aldehyde building blocks.
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Imidazóis/síntese química , Pirimidinas/síntese química , Aldeídos/química , Catálise , Imidazóis/química , Estrutura Molecular , Pirimidinas/química , EstereoisomerismoRESUMO
The complex multistep activation cascade of Ire1 involves changes in the Ire1 conformation and oligomeric state. Ire1 activation enhances ER folding capacity, in part by overexpressing the ER Hsp70 molecular chaperone BiP; in turn, BiP provides tight negative control of Ire1 activation. This study demonstrates that BiP regulates Ire1 activation through a direct interaction with Ire1 oligomers. Particularly, we demonstrated that the binding of Ire1 luminal domain (LD) to unfolded protein substrates not only trigger conformational changes in Ire1-LD that favour the formation of Ire1-LD oligomers but also exposes BiP binding motifs, enabling the molecular chaperone BiP to directly bind to Ire1-LD in an ATP-dependent manner. These transient interactions between BiP and two short motifs in the disordered region of Ire1-LD are reminiscent of interactions between clathrin and another Hsp70, cytoplasmic Hsc70. BiP binding to substrate-bound Ire1-LD oligomers enables unfolded protein substrates and BiP to synergistically and dynamically control Ire1-LD oligomerisation, helping to return Ire1 to its deactivated state when an ER stress response is no longer required.
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Chaperona BiP do Retículo Endoplasmático , Estresse do Retículo Endoplasmático , Endorribonucleases , Proteínas de Choque Térmico , Ligação Proteica , Proteínas Serina-Treonina Quinases , Proteínas Serina-Treonina Quinases/metabolismo , Chaperona BiP do Retículo Endoplasmático/metabolismo , Proteínas de Choque Térmico/metabolismo , Proteínas de Choque Térmico/química , Endorribonucleases/metabolismo , Endorribonucleases/química , Humanos , Retículo Endoplasmático/metabolismo , Resposta a Proteínas não Dobradas , Multimerização Proteica , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP70/química , Dobramento de Proteína , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/química , Domínios ProteicosRESUMO
Extracellular matrix (ECM) remodeling is strongly linked to Alzheimer's disease (AD) risk; however, the underlying mechanisms are not fully understood. Here, it is found that the injection of chondroitinase ABC (ChABC), mimicking ECM remodeling, into the medial prefrontal cortex (mPFC) reversed short-term memory loss and reduced amyloid-beta (Aß) deposition in 5xFAD mice. ECM remodeling also reactivated astrocytes, reduced the levels of aggrecan in Aß plaques, and enhanced astrocyte recruitment to surrounding plaques. Importantly, ECM remodeling enhanced the autophagy-lysosome pathway in astrocytes, thereby mediating Aß clearance and alleviating AD pathology. ECM remodeling also promoted Aß plaque phagocytosis by astrocytes by activating the astrocytic phagocytosis receptor MERTK and promoting astrocytic vesicle circulation. The study identified a cellular mechanism in which ECM remodeling activates the astrocytic autophagy-lysosomal pathway and alleviates AD pathology. Targeting ECM remodeling may represent a potential therapeutic strategy for AD and serve as a reference for the treatment of this disease.
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Doença de Alzheimer , Astrócitos , Autofagia , Modelos Animais de Doenças , Matriz Extracelular , Lisossomos , Transtornos da Memória , Animais , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Astrócitos/metabolismo , Camundongos , Matriz Extracelular/metabolismo , Lisossomos/metabolismo , Transtornos da Memória/metabolismo , Camundongos Transgênicos , MasculinoRESUMO
De novo design has been a hotly pursued topic for many years. Most recent developments have involved the use of deep learning methods for generative molecular design. Despite increasing levels of algorithmic sophistication, the design of molecules that are synthetically accessible remains a major challenge. Reaction-based de novo design takes a conceptually simpler approach and aims to address synthesisability directly by mimicking synthetic chemistry and driving structural transformations by known reactions that are applied in a stepwise manner. However, the use of a small number of hand-coded transformations restricts the chemical space that can be accessed and there are few examples in the literature where molecules and their synthetic routes have been designed and executed successfully. Here we describe the application of reaction-based de novo design to the design of synthetically accessible and biologically active compounds as proof-of-concept of our reaction vector-based software. Reaction vectors are derived automatically from known reactions and allow access to a wide region of synthetically accessible chemical space. The design was aimed at producing molecules that are active against PARP1 and which have improved brain penetration properties compared to existing PARP1 inhibitors. We synthesised a selection of the designed molecules according to the provided synthetic routes and tested them experimentally. The results demonstrate that reaction vectors can be applied to the design of novel molecules of biological relevance that are also synthetically accessible.
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Desenho de Fármacos , Inibidores de Poli(ADP-Ribose) Polimerases , Inibidores de Poli(ADP-Ribose) Polimerases/química , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/síntese química , Humanos , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Poli(ADP-Ribose) Polimerase-1/metabolismo , SoftwareRESUMO
Human mesenchymal stem cells (hMSCs) have been shown to have potential in regenerative approaches in bone and blood. Most protocols rely on their in vitro expansion prior to clinical use. However, several groups including our own have shown that hMSCs lose proliferation and differentiation ability with serial passage in culture, limiting their clinical applications. Cellular prion protein (PrP) has been shown to enhance proliferation and promote self-renewal of hematopoietic, mammary gland, and neural stem cells. Here we show, for the first time, that expression of PrP decreased in hMSC following ex vivo expansion. When PrP expression was knocked down, hMSC showed significant reduction in proliferation and differentiation. In contrast, hMSC expanded in the presence of small molecule 3/689, a modulator of PrP expression, showed retention of PrP expression with ex vivo expansion and extended lifespan up to 10 population doublings. Moreover, cultures produced a 300-fold increase in the number of cells generated. These cells showed a 10-fold increase in engraftment levels in bone marrow 5 weeks post-transplant. hMSC treated with 3/689 showed enhanced protection from DNA damage and enhanced cell cycle progression, in line with data obtained by gene expression profiling. Moreover, upregulation of superoxide dismutase-2 (SOD2) was also observed in hMSC expanded in the presence of 3/689. The increase in SOD2 was dependent on PrP expression and suggests increased scavenging of reactive oxygen species as mechanism of action. These data point to PrP as a good target for chemical intervention in stem cell regenerative medicine.
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Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/citologia , Príons/biossíntese , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/metabolismo , Diferenciação Celular/fisiologia , Processos de Crescimento Celular/fisiologia , Células Cultivadas , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Lentivirus/genética , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/fisiologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Fosforilação , Príons/genética , TransfecçãoRESUMO
A novel protocol based on size-exclusion chromatography (SEC) and MS was established to accelerate dynamic combinatorial chemistry (DCC) in this study. By isolating ligand-target adducts from the dynamic combinatorial library (DCL), ligands could be identified directly by MS after denaturation. Three new inhibitors for lysozyme were discovered by this SEC-MS protocol in a case study. Km Data for these new inhibitors was also determined.
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Técnicas de Química Combinatória , Inibidores Enzimáticos/farmacologia , Muramidase/antagonistas & inibidores , Animais , Galinhas , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Ligantes , Estrutura Molecular , Muramidase/metabolismo , Relação Estrutura-AtividadeRESUMO
Reaction-based de novo design refers to the generation of synthetically accessible molecules using transformation rules extracted from known reactions in the literature. In this context, we have previously described the extraction of reaction vectors from a reactions database and their coupling with a structure generation algorithm for the generation of novel molecules from a starting material. An issue when designing molecules from a starting material is the combinatorial explosion of possible product molecules that can be generated, especially for multistep syntheses. Here, we present the development of RENATE, a reaction-based de novo design tool, which is based on a pseudo-retrosynthetic fragmentation of a reference ligand and an inside-out approach to de novo design. The reference ligand is fragmented; each fragment is used to search for similar fragments as building blocks; the building blocks are combined into products using reaction vectors; and a synthetic route is suggested for each product molecule. The RENATE methodology is presented followed by a retrospective validation to recreate a set of approved drugs. Results show that RENATE can generate very similar or even identical structures to the corresponding input drugs, hence validating the fragmentation, search, and design heuristics implemented in the tool.
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Algoritmos , Ligantes , Estudos RetrospectivosRESUMO
A significant intersection between antimalarial and antiprion activity is well established for certain compound classes, specifically for polycyclic antimalarial agents bearing basic nitrogen-containing sidechains (e.g., chloroquine, quinacrine, mefloquine). Screening a recently reported set of antiprion compounds with such sidechains showed these 2,4-diarylthiazole based structures also possess significant antimalarial activity. Of particular note, all but one of the compounds displayed activity against a chloroquine-resistant Plasmodium falciparum strain, identifying them as interesting leads for further development in this context. In addition, three new members of the series showed superior antiprion activity compared to the earlier-reported compounds.
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Antimaláricos/síntese química , Antimaláricos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Príons/antagonistas & inibidores , Tiazóis/síntese química , Antimaláricos/química , Cloroquina/química , Cloroquina/farmacologia , Mefloquina/química , Mefloquina/farmacologia , Estrutura Molecular , Quinacrina/química , Quinacrina/farmacologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
The extensive production and large-scale use of perfluoroalkyl substances (PFASs) have raised their presence in aquatic environments worldwide. Thus, the facile and reliable screening of PFASs in aqueous systems is of great significance. Herein, we designed a novel fluorescent sensor array for the rapid screening and discrimination of multiple PFASs in water. The sensor array comprised three highly stable zirconium porphyrinic luminescent metal-organic frameworks (i.e., PCNs) with different topological structures. The sensing mechanism was based on the static fluorescence quenching of PCNs by PFASs upon their adsorptive interactions. The fluorescence response patterns were characteristic for each PFAS because of their different adsorption affinities toward different PCNs. Through the interpretation of response patterns by statistical methods, the proposed PCN array successfully discriminated six different kinds of PFASs, each PFAS at different concentrations and PFAS mixtures at different molar ratios. The practicability of this array was further verified by effectively discriminating PFASs in two real water samples. Remarkably, the PCN sensors exhibited a very short response time toward PFASs (within 10 s) due to the ordered pore structure allowing fast PFAS diffusion. This study not only provides a facile method for rapid PFAS screening in waters but also broadens the application of luminescent metal-organic frameworks and array techniques in sensing fields.
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The development of a rapid and sensitive method for the detection of fluoride ion (F-) in aqueous systems is of great significance for human health and environmental monitoring. In this study, a zirconium porphyrinic luminescent metal-organic framework (LMOF), PCN-222, was employed as a novel fluorescent probe for the ultrasensitive, rapid and selective detection of F- in water. The PCN-222 probe was prepared by a facile solvothermal method. It exhibited good fluorescence stability and was highly stable in water. The fluorescence emission of PCN-222 could be effectively and selectively quenched by F- due to the strong coordination affinity of F- to the zirconium clusters in PCN-222. The proposed fluorescence method for F- detection based on PCN-222 probe afforded a linear response range of 1-20 µmol/L and a very low detection limit (0.048-0.065 µmol/L) in reference to many reported F- fluorescent probes. Moreover, a rapid response time (<10 s) was obtained due to the open and uniform pore structure of PCN-222 that allowed the fast diffusion of F- to interact with the zirconium recognition sites. Finally, the PCN-222 probe was successfully applied for the fluorescence detection of F- in real water samples. These results highlight the great application potential of LMOF in the sensing fields.
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BACKGROUND: The corosolic acid (CA), also known as plant insulin, is a pentacyclic triterpenoid extracted from plants such as Lagerstroemia speciosa. It has been shown to have anti-diabetic, anti-inflammatory and anti-tumor effects. Its structural analogs ursolic acid (UA), oleanolic acid (OA), maslinic acid (MA), asiatic acid (AA) and betulinic acid (BA) display similar individual pharmacological activities to those of CA. However, there is no systematic review documenting pharmacological activities of CA and its structural analogues. This study aims to fill this gap in literature. PURPOSE: This systematic review aims to summarize the medical applications of CA and its analogues. METHODS: A systematic review summarizes and compares the extraction techniques, pharmacokinetic parameters, and pharmacological effects of CA and its structural analogs. Hypoglycemic effect is one of the key inclusion criteria for searching Web of Science, PubMed, Embase and Cochrane databases up to October 2020 without language restrictions. 'corosolic acid', 'ursolic acid', 'oleanolic acid', 'maslinic acid', 'asiatic acid', 'betulinic acid', 'extraction', 'pharmacokinetic', 'pharmacological' were used to extract relevant literature. The PRISMA guidelines were followed. RESULTS: At the end of the searching process, 140 articles were selected for the systematic review. Information of CA and five of its structural analogs including UA, OA, MA, AA and BA were included in this review. CA and its structural analogs are pentacyclic triterpenes extracted from plants and they have low solubilities in water due to their rigid scaffold and hydrophobic properties. The introduction of water-soluble groups such as sugar or amino groups could increase the solubility of CA and its structural analogs. Their biological activities and underlying mechanism of action are reviewed and compared. CONCLUSION: CA and its structural analogs UA, OA, MA, AA and BA are demonstrated to show activities in lowering blood sugar, anti-inflammation and anti-tumor. Their oral absorption and bioavailability can be improved through structural modification and formulation design. CA and its structural analogs are promising natural product-based lead compounds for further development and mechanistic studies.
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Ácido Oleanólico , Triterpenos , Anti-Inflamatórios/farmacologia , Hipoglicemiantes/farmacologia , Ácido Oleanólico/farmacologia , Triterpenos/farmacologiaRESUMO
Amyloid ß oligomers (Aßo) are the main toxic species in Alzheimer's disease, which have been targeted for single drug treatment with very little success. In this work we report a new approach for identifying functional Aßo binding compounds. A tailored library of 971 fluorine containing compounds was selected by a computational method, developed to generate molecular diversity. These compounds were screened for Aßo binding by a combined 19F and STD NMR technique. Six hits were evaluated in three parallel biochemical and functional assays. Two compounds disrupted Aßo binding to its receptor PrPC in HEK293 cells. They reduced the pFyn levels triggered by Aßo treatment in neuroprogenitor cells derived from human induced pluripotent stem cells (hiPSC). Inhibitory effects on pTau production in cortical neurons derived from hiPSC were also observed. These drug-like compounds connect three of the pillars in Alzheimer's disease pathology, i.e. prion, Aß and Tau, affecting three different pathways through specific binding to Aßo and are, indeed, promising candidates for further development.
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A Bayesian inference network (BIN) provides an interesting alternative to existing tools for similarity-based virtual screening. The BIN is particularly effective when the active molecules being sought have a high degree of structural homogeneity but has been found to perform less well with structurally heterogeneous sets of actives. In this paper, we introduce an alternative network model, called a Bayesian belief network (BBN), that seeks to overcome this limitation of the BIN approach. Simulated virtual screening experiments with the MDDR, WOMBAT and MUV data sets show that the BIN and BBN methods allow effective screening searches to be carried out. However, the results obtained are not obviously superior to those obtained using a much simpler approach that is based on the use of the Tanimoto coefficient and of the square roots of fragment occurrence frequencies.
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Avaliação Pré-Clínica de Medicamentos/métodos , Interface Usuário-Computador , Teorema de Bayes , Ligantes , Proteínas/metabolismoRESUMO
Despite the rapidly increasing number of patients suffering from type 2 diabetes, Alzheimer's disease, and diabetes-induced dementia, there are no disease-modifying therapies that are able to prevent or block disease progress. In this work, we investigate the potential of nature-inspired glucosylpolyphenols against relevant targets, including islet amyloid polypeptide, glucosidases, and cholinesterases. Moreover, with the premise of Fyn kinase as a paradigm-shifting target in Alzheimer's drug discovery, we explore glucosylpolyphenols as blockers of Aß-induced Fyn kinase activation while looking into downstream effects leading to Tau hyperphosphorylation. Several compounds inhibit Aß-induced Fyn kinase activation and decrease pTau levels at 10 µM concentration, particularly the per-O-methylated glucosylacetophloroglucinol and the 4-glucosylcatechol dibenzoate, the latter inhibiting also butyrylcholinesterase and ß-glucosidase. Both compounds are nontoxic with ideal pharmacokinetic properties for further development. This work ultimately highlights the multitarget nature, fine structural tuning capacity, and valuable therapeutic significance of glucosylpolyphenols in the context of these metabolic and neurodegenerative disorders.