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1.
J Mol Model ; 27(2): 26, 2021 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-33410998

RESUMO

Flavonoids are a big class of natural product and have a wide range of biological activities. Some of these applications depend on its antioxidant capacity. Nevertheless, another mechanism can be involved by means of alkylation reaction on α,ß-unsaturated carbonyl system. This study aimed to evaluate the antioxidant capacity and the chemical reactivity among simplified flavonoid derivatives and isoxazolone analogous as Michael system by using B3LYP functional and 6-311 g(d,p) basis set. Frontier molecular orbital, ionization potential (IP), spin density contributions, and Fukui index explain the antioxidant capacity and reactivity index on isoxazolone and its related derivatives. The best contribution at ß-alkene moiety is related to better reactivity of α,ß-unsaturated carbonyl group. A decrease in antioxidant capacity is related to an increase in the chemical reactivity index. The frontier molecular orbitals show that aurone is more reactive than isoxazolone. In accordance with Fukui index, isoxazolone can be better inhibitor as Michael system when compared to flavonoid derivatives. Graphical abstract.


Assuntos
Flavonoides/química , Oxazóis/química , Teoria da Densidade Funcional , Modelos Moleculares
2.
J Mol Model ; 26(11): 318, 2020 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-33099704

RESUMO

A hypothetical study by using molecular modeling for antioxidant capacity of kojic acid derivatives was performed using quantum chemistry calculations by DFT/B3LYP/6-311++G(3d,2p). Four modification approaches were considered namely simplification, functional modifications, ring regioisomerism, and hydroxylation. Molecular orbitals, single-electron transfers, hydrogen atom transfers, and spin density distributions were used for antioxidant prediction. In accordance with HOMO, LUMO, Gap, ionization potential, bond dissociation energy, and stabilization energy, the molecular simplifications of kojic acid show that enol moiety is more important for antioxidant capacity than alcohol group. Few molecular modifications on alcohol or enol position were more potent than kojic acid. The π conjugation system among ether, alkene, and hydroxyl moieties can be involved on resonance effects of better compounds. A different performance was observed on alcohol molecular modifications when compared to enol position. All lactone derivatives were more potent than kojic acid on both mechanisms, and their hydroxylated derivatives were more potent than ascorbic acid. In conclusion, the ring regioisomers and its hydroxylated derivatives have better antioxidant capacity than kojic acid. Graphical Abstract The theoretical study using molecular modeling for antioxidant capacity prediction of kojic acid was more related to enol moiety than alcohol. The regioisomerism and hybrid derivatives show that the lactone derivatives increase antioxidant capacity more than the pyrone derivatives.

3.
Molecules ; 25(5)2020 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-32164183

RESUMO

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.


Assuntos
Receptores A2 de Adenosina/metabolismo , Adenosina/análogos & derivados , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular/métodos , Simulação de Dinâmica Molecular , Relação Quantitativa Estrutura-Atividade
4.
Molecules ; 24(8)2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30991684

RESUMO

Inflammation is a complex reaction involving cellular and molecular components and an unspecific response to a specific aggression. The use of scientific and technological innovations as a research tool combining multidisciplinary knowledge in informatics, biotechnology, chemistry and biology are essential for optimizing time and reducing costs in the drug design. Thus, the integration of these in silico techniques makes it possible to search for new anti-inflammatory drugs with better pharmacokinetic and toxicological profiles compared to commercially used drugs. This in silico study evaluated the anti-inflammatory potential of two benzoylpropionic acid derivatives (MBPA and DHBPA) using molecular docking and their thermodynamic profiles by molecular dynamics, in addition to predicting oral bioavailability, bioactivity and toxicity. In accordance to our predictions the derivatives proposed here had the potential capacity for COX-2 inhibition in the human and mice enzyme, due to containing similar interactions with the control compound (ibuprofen). Ibuprofen showed toxic predictions of hepatotoxicity (in human, mouse and rat; toxicophoric group 2-arylacetic or 3-arylpropionic acid) and irritation of the gastrointestinal tract (in human, mouse and rat; toxicophoric group alpha-substituted propionic acid or ester) confirming the literature data, as well as the efficiency of the DEREK 10.0.2 program. Moreover, the proposed compounds are predicted to have a good oral bioavailability profile and low toxicity (LD50 < 700 mg/kg) and safety when compared to the commercial compound. Therefore, future studies are necessary to confirm the anti-inflammatory potential of these compounds.


Assuntos
Anti-Inflamatórios não Esteroides/química , Benzoatos/química , Simulação por Computador , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/química , Ibuprofeno/química , Simulação de Acoplamento Molecular , Propionatos/química , Animais , Humanos , Camundongos , Ratos
5.
Molecules ; 23(2)2018 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-29463017

RESUMO

The Protein Kinase Receptor type 2 (RIPK2) plays an important role in the pathogenesis of inflammatory diseases; it signals downstream of the NOD1 and NOD2 intracellular sensors and promotes a productive inflammatory response. However, excessive NOD2 signaling has been associated with various diseases, including sarcoidosis and inflammatory arthritis; the pharmacological inhibition of RIPK2 is an affinity strategy that demonstrates an increased expression of pro-inflammatory secretion activity. In this study, a pharmacophoric model based on the crystallographic pose of ponatinib, a potent RIPK2 inhibitor, and 30 other ones selected from the BindingDB repository database, was built. Compounds were selected based on the available ZINC compounds database and in silico predictions of their pharmacokinetic, toxicity and potential biological activity. Molecular docking was performed to identify the probable interactions of the compounds as well as their binding affinity with RIPK2. The compounds were analyzed to ponatinib and WEHI-345, which also used as a control. At least one of the compounds exhibited suitable pharmacokinetic properties, low toxicity and an interesting binding affinity and high fitness compared with the crystallographic pose of WEHI-345 in complex with RIPK2. This compound also possessed suitable synthetic accessibility, rendering it a potential and very promising RIPK2 inhibitor to be further investigated in regards to different diseases, particularly inflammatory ones.


Assuntos
Imidazóis/química , Inflamação/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Piridazinas/química , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/antagonistas & inibidores , Cristalografia por Raios X , Humanos , Imidazóis/uso terapêutico , Simulação de Acoplamento Molecular , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/química , Transdução de Sinais/efeitos dos fármacos , Interface Usuário-Computador
6.
Molecules ; 19(8): 10670-97, 2014 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-25061720

RESUMO

The Density Functional Theory (DFT) method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with different degrees of cytotoxicity against the human hepatocellular carcinoma HepG2 line. Principal component analysis (PCA) and hierarchical cluster analysis (HCA) were employed to select the most important descriptors related to anticancer activity. The significant molecular descriptors related to the compounds with anticancer activity were the ALOGPS_log, Mor29m, IC5 and GAP energy. The Pearson correlation between activity and most important descriptors were used for the regression partial least squares (PLS) and principal component regression (PCR) models built. The regression PLS and PCR were very close, with variation between PLS and PCR of R(2) = ± 0.0106, R(2)(ajust) = ± 0.0125, s = ± 0.0234, F(4,11) = ± 12.7802, Q(2) = ± 0.0088, SEV = ± 0.0132, PRESS = ± 0.4808 and SPRESS = ± 0.0057. These models were used to predict the anticancer activity of eight new artemisinin compounds (test set) with unknown activity, and for these new compounds were predicted pharmacokinetic properties: human intestinal absorption (HIA), cellular permeability (PCaCO2), cell permeability Maden Darby Canine Kidney (PMDCK), skin permeability (P(Skin)), plasma protein binding (PPB) and penetration of the blood-brain barrier (C(Brain/Blood)), and toxicological: mutagenicity and carcinogenicity. The test set showed for two new artemisinin compounds satisfactory results for anticancer activity and pharmacokinetic and toxicological properties. Consequently, further studies need be done to evaluate the different proposals as well as their actions, toxicity, and potential use for treatment of cancers.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Relação Quantitativa Estrutura-Atividade , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/toxicidade , Artemisininas/farmacocinética , Artemisininas/toxicidade , Linhagem Celular , Linhagem Celular Tumoral , Análise por Conglomerados , Células Hep G2 , Humanos , Estrutura Molecular , Permeabilidade , Distribuição Tecidual
7.
Molecules ; 19(1): 367-99, 2013 Dec 30.
Artigo em Inglês | MEDLINE | ID: mdl-24381053

RESUMO

The Hartree-Fock method and the 6-31G** basis set were employed to calculate the molecular properties of artemisinin and 20 derivatives with antimalarial activity. Maps of molecular electrostatic potential (MEPs) and molecular docking were used to investigate the interaction between ligands and the receptor (heme). Principal component analysis and hierarchical cluster analysis were employed to select the most important descriptors related to activity. The correlation between biological activity and molecular properties was obtained using the partial least squares and principal component regression methods. The regression PLS and PCR models built in this study were also used to predict the antimalarial activity of 30 new artemisinin compounds with unknown activity. The models obtained showed not only statistical significance but also predictive ability. The significant molecular descriptors related to the compounds with antimalarial activity were the hydration energy (HE), the charge on the O11 oxygen atom (QO11), the torsion angle O1-O2-Fe-N2 (D2) and the maximum rate of R/Sanderson Electronegativity (RTe+). These variables led to a physical and structural explanation of the molecular properties that should be selected for when designing new ligands to be used as antimalarial agents.


Assuntos
Antimaláricos/química , Antimaláricos/farmacologia , Artemisininas/química , Artemisininas/farmacologia , Análise por Conglomerados , Heme/química , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Análise de Componente Principal , Relação Quantitativa Estrutura-Atividade , Eletricidade Estática , Relação Estrutura-Atividade
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