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1.
Molecules ; 28(8)2023 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-37110831

RESUMO

Multi-target drug development has become an attractive strategy in the discovery of drugs to treat of Alzheimer's disease (AzD). In this study, for the first time, a rule-based machine learning (ML) approach with classification trees (CT) was applied for the rational design of novel dual-target acetylcholinesterase (AChE) and ß-site amyloid-protein precursor cleaving enzyme 1 (BACE1) inhibitors. Updated data from 3524 compounds with AChE and BACE1 measurements were curated from the ChEMBL database. The best global accuracies of training/external validation for AChE and BACE1 were 0.85/0.80 and 0.83/0.81, respectively. The rules were then applied to screen dual inhibitors from the original databases. Based on the best rules obtained from each classification tree, a set of potential AChE and BACE1 inhibitors were identified, and active fragments were extracted using Murcko-type decomposition analysis. More than 250 novel inhibitors were designed in silico based on active fragments and predicted AChE and BACE1 inhibitory activity using consensus QSAR models and docking validations. The rule-based and ML approach applied in this study may be useful for the in silico design and screening of new AChE and BACE1 dual inhibitors against AzD.


Assuntos
Acetilcolinesterase , Doença de Alzheimer , Humanos , Acetilcolinesterase/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Inibidores da Colinesterase/química , Simulação de Acoplamento Molecular , Secretases da Proteína Precursora do Amiloide , Ácido Aspártico Endopeptidases , Precursor de Proteína beta-Amiloide
2.
Environ Dev Sustain ; : 1-46, 2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35966336

RESUMO

We are the first to empirically analyze the nexus of digital transformation and energy security (ES). This paper utilizes six indicators to reflect three aspects of ES, including acceptability, develop-ability, and sustainability. Applying the panel-corrected standard errors (PCSEs) and the feasible generalized least square estimates (FGLS) model to the international sample of 27 European countries over 2015 to 2019, this research reveals exciting findings. First, a promotion in digital transformation causes a significantly positive effect on the acceptability and sustainability of ES but a negative impact on develop-ability of ES. Second, the ES positively affects the digital transformation, especially the digital transformation in the business and public sectors. Third, results obtained from the dynamic fixed effects (DFEs) estimator for the autoregressive distributed lag (ARDL) method suggest that setting ES goals toward reducing energy consumption and pollution emission promotes the digital transformation process in the business sector of countries in the short run, while the promotion of renewable energy consumption helps countries enhance the digitalization process in the long run. Notably, digitalization is beneficial for sustainable economic development, reflected by a rise in non-fossil and renewable energy consumption and a diminish in CO2 emission, especially in the long run. Fourth, there is a nonlinear effect of the online transaction and digital public services on the acceptability, develop-ability, and sustainability of ES. In a similar spirit, the digital transformation is also accelerated more quickly if the efficiency of the energy system reaches a certain point.

3.
Bioorg Chem ; 71: 160-169, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28196602

RESUMO

In our search for novel small molecules targeting histone deacetylases, we have designed and synthesized two series of novel N-hydroxybenzamides incorporating 2-oxoindolines (4a-g, 6a-g). Biological evaluation showed that these benzamides potently inhibited HDAC2 with IC50 values in sub-micromolar range. In three human cancer cell lines the synthesized compounds were up to 4-fold more cytotoxic than SAHA. Docking experiments indicated that the compounds tightly bound to HDAC2 at the active binding site with binding affinities much higher than that of SAHA. Our present results demonstrate that these novel and simple N-hydroxybenzamides are potential for further development as anticancer agents and further investigation of similarly simple N-hydroxybenzamides should be warranted to obtain more potent HDAC inhibitors.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Histona Desacetilase 2/antagonistas & inibidores , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/farmacologia , Indóis/química , Indóis/farmacologia , Antineoplásicos/síntese química , Benzamidas/síntese química , Benzamidas/química , Benzamidas/farmacologia , Linhagem Celular Tumoral , Química Click , Cristalografia por Raios X , Ensaios de Seleção de Medicamentos Antitumorais , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/síntese química , Histona Desacetilases/metabolismo , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Ácidos Hidroxâmicos/farmacologia , Indóis/síntese química , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Relação Estrutura-Atividade
4.
Med Chem ; 11(3): 296-304, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25256241

RESUMO

The search for newer histone deacetylase (HDAC) inhibitors has attracted a great deal of interest of medicinal chemists worldwide, especially after the first HDAC inhibitor (Zolinza(®), widely known as SAHA or Suberoylanilide hydroxamic acid) was approved by the FDA for the treatment of Tcell lymphoma in 2006. As a continuity of our ongoing research in this area, we designed and synthesized a series of 5-aryl-1,3,4-thiadiazole-based hydroxamic acids as analogues of SAHA and evaluated their biological activities. Most of the compounds in this series, e.g. compounds with 5-aryl moiety being 2- furfuryl (5a), 5-bromofuran-2-yl (5b), 5-methylfuran-2-yl (5c), thiophen-2-yl (5d), 5-methylthiophen-2-yl (5f) and pyridyl (5g-i), were found to have potent anticancer cytotoxicity with IC50 values of generally 5- to 10-fold lower than that of SAHA in 4 human cancer cell lines assayed. Those compounds with potent cytotoxicity were also found to have strong HDAC inhibition effects. Docking studies revealed that compounds 5a and 5d displayed high affinities towards HDAC2 and 8.


Assuntos
Antineoplásicos/farmacologia , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Ácidos Hidroxâmicos/farmacologia , Simulação de Acoplamento Molecular , Tiadiazóis/química , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Humanos , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/química , Células MCF-7 , Estrutura Molecular , Relação Estrutura-Atividade
5.
Nat Prod Commun ; 4(3): 323-5, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19413107

RESUMO

From the methanolic extract of the roots of Clerodendrum philipinum, a new rearranged abietane diterpene (1) and eight known compounds were isolated by various chromatography methods. Their structures were identified by means of spectroscopic methods, including 1D- and 2D-NMR, as 17(15-->16),18(4-->3)-bisabeo-11,12,14,16-tetrahydroxy-3,5,8,11,13,15-abietahexaen-7-one (1), binankadsurin A, clerodenoside A, martynoside, acteoside, isoacteoside, astragalin, p3-sitosterol, and daucosterol. Binankadsurin A was found for the first time from a Clerodendrum species.


Assuntos
Abietanos/análise , Abietanos/isolamento & purificação , Clerodendrum/química , Lignanas/análise , Lignanas/isolamento & purificação , Cromatografia , Glucosídeos/isolamento & purificação , Quempferóis/isolamento & purificação , Espectroscopia de Ressonância Magnética , Metanol , Estrutura Molecular , Fenóis/isolamento & purificação , Sitosteroides/isolamento & purificação
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