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1.
Comput Biol Chem ; 79: 119-126, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30785021

RESUMO

Gp41 and its conserved hydrophobic groove on the NHR region is one of the attractive targets in the design of HIV-1 entry inhibitory agents. This hydrophobic pocket is very critical for the progression of HIV and host cell fusion. In this study different ligand-based (structure similarity search) and structure-based (molecular docking and molecular dynamic simulation) methods were performed in a virtual screening procedure to select the best compounds with the most probable HIV-1 gp41 inhibitory activities. In silico pharmacokinetics and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties filtration also was considered to choose the compounds with best drug-like properties. The results of molecular docking and molecular dynamic simulations of the final selected compounds showed suitable stabilities of their complexes with gp41. The final selected hits could have better pharmacokinetics properties than the template compound, theaflavin digallate (TF3), a naturally-originated potent gp41 inhibitor.


Assuntos
Biflavonoides/farmacologia , Catequina/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Proteína gp41 do Envelope de HIV/antagonistas & inibidores , Realidade Virtual , Biflavonoides/química , Catequina/química , Humanos , Ligantes , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade
2.
J Food Sci ; 80(10): H2336-45, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26351865

RESUMO

Fibrillation of alpha-synuclein (α-SN) is a critical process in the pathophysiology of several neurodegenerative diseases, especially Parkinson's disease. Application of bioactive inhibitory compounds from herbal extracts is a potential therapeutic approach for this cytotoxic process. Here, we investigated the inhibitory effects of the Iranian Cuminum cyminum essential oil on the fibrillation of α-SN. Analysis of different fractions from the total extract identified cuminaldehyde as the active compound involved in the antifibrillation activity. In comparison with baicalein, a well-known inhibitor of α-SN fibrillation, cuminaldehyde showed the same activity in some aspects and a different activity on other parameters influencing α-SN fibrillation. The presence of spermidine, an α-SN fibrillation inducer, dominantly enforced the inhibitory effects of cuminaldehyde even more intensively than baicalein. Furthermore, the results from experiments using preformed fibrils and monobromobimane-labeled monomeric protein also suggest that cuminaldehyde prevents α-SN fibrillation even in the presence of seeds, having no disaggregating impact on the preformed fibrils. Structural studies showed that cuminaldehyde stalls protein assembly into ß-structural fibrils, which might be achieved by the interaction with amine groups through its aldehyde group as a Schiff base reaction. This assumption was supported by FITC labeling efficiency assay. In addition, cytotoxicity assays on PC12 cells showed that cuminaldehyde is a nontoxic compound, treatment with cuminaldehyde throughout α-SN fibrillation showed no toxic effects on the cells. Taken together, these results show for the first time that the small abundant natural compound, cuminaldehyde, can modulate α-SN fibrillation. Hence, suggesting that such natural active aldehyde could have potential therapeutic applications.


Assuntos
Benzaldeídos/farmacologia , Cuminum/química , Doença de Parkinson , Extratos Vegetais/farmacologia , alfa-Sinucleína/metabolismo , Animais , Benzaldeídos/efeitos adversos , Benzaldeídos/química , Cimenos , Flavanonas/farmacologia , Óleos Voláteis/administração & dosagem , Óleos Voláteis/química , Óleos Voláteis/farmacologia , Células PC12 , Doença de Parkinson/fisiopatologia , Extratos Vegetais/efeitos adversos , Extratos Vegetais/química , Conformação Proteica/efeitos dos fármacos , Ratos , Sementes/química
3.
J Mol Model ; 18(9): 4309-24, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22570080

RESUMO

Selective A(2B) receptor antagonists and agonists may play a role in important pathologies such as gastrointestinal, neurological (i.e., Alzheimer disease and dementia) and hypersensitive disorders (i.e., asthma), diabetes, atherosclerosis, restenosis and cancer. Hence, it is regarded as a good target for the development of clinically useful agents. In this study, the effects of lipid bilayer, N-acetylglucosamine and S-palmitoyl on the dynamic behavior of A(2B)AR model is explored. Homology modeling, molecular docking and molecular dynamics simulations were performed to explore structural features of A(2B)AR in the presence of lipid bilayer. Twenty ns MD simulation was performed on the constructed model inserted in a hydrated lipid bilayer to examine stability of the best model. OSIP339391 as the most potent antagonist was docked in the active site of the model. Another MD simulation was performed on the ligand-protein complex to explore effects of the bilayer on this complex. A similar procedure was performed for the modified protein with N-acetylglucosamine and S-palmitoyl moieties in its structure. Phe173 and Glu174 located in EL2 were determined to be involved in ligand-receptor interactions through π-π stacking and hydrogen bonding. Asn254 was crucial to form hydrogen-bonding. The reliability of the model was assessed through docking using both commercial and synthetic antagonists and an r(2) of 0.70 was achieved. Our results show that molecular dynamics simulations of palmitoylated/glycosylated, membrane-integrated human A(2B)AR in its native environment is a possible approach and this model can be used for designing potent and selective A(2B)AR antagonists.


Assuntos
Membrana Celular/metabolismo , Lipoilação , Simulação de Dinâmica Molecular , Receptores Adrenérgicos alfa 2/química , Receptores Adrenérgicos alfa 2/metabolismo , Sítios de Ligação , Membrana Celular/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Glicosilação , Humanos , Antagonistas de Receptores Purinérgicos P1/análise , Antagonistas de Receptores Purinérgicos P1/farmacologia , Homologia Estrutural de Proteína , Interface Usuário-Computador
4.
Int J Colorectal Dis ; 25(10): 1159-65, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20669022

RESUMO

BACKGROUND: Anti-inflammatory drugs with high potency and low systemic adverse effects, such as budesonide, are drugs of choice for the treatment of ulcerative colitis (UC). Budesonide controlled-release formulations are now being used to induce and maintain clinical remission of Crohn's disease. Budesonide-dextran conjugates were synthesized as novel prodrugs of budesonide for oral controlled delivery of the major part of the drug to the colon without needing to coat the pellets of the drug. The aim of this study was to evaluate the in vivo efficacy of this conjugate against acetic acid-induced colitis in rats. MATERIALS AND METHODS: Experimental UC was induced by rectal instillation of 4% solution of acetic acid to rats. After induction of colitis, rats were treated with vehicle (dextran solution), mesalasine (120 mg/kg), budesonide suspension (300 microg/kg) and BSD-70 (equivalent to 300 microg/kg of budesonide), prednisolon (4 mg/kg), hydrocortisone acetate enema (20 mg/kg), and 5-ASA enema (Asacol) (400 mg/kg) for 5 days and then colon macroscopic and microscopic sections were examined for inflammatory response. RESULTS: Vehicle-treated rats presented bloody diarrhoea and gross lesions. The effective formulations for attenuating the damage were BSD-70, oral prednisolon and hydrocortisone acetate enema. Rats treated with BSD-70 showed huge improvement in macroscopic and histological scores of colitis compared to the negative control group and mesalasine and budesonide suspension. CONCLUSION: Data indicated that budesonide-dextran conjugate is effective in improving signs of inflammation in experimental model of colitis through selective delivery of the drug to the inflamed area.


Assuntos
Budesonida/administração & dosagem , Colite/tratamento farmacológico , Pró-Fármacos/química , Ácido Acético/efeitos adversos , Animais , Anti-Inflamatórios , Budesonida/uso terapêutico , Colite/induzido quimicamente , Dextranos , Hidrocortisona/análogos & derivados , Hidrocortisona/uso terapêutico , Masculino , Prednisolona/uso terapêutico , Pró-Fármacos/uso terapêutico , Ratos , Ratos Wistar , Ácido Succínico
5.
Bioorg Med Chem ; 16(17): 8254-63, 2008 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-18693021

RESUMO

A group of beta-phenylethylidenehydrazines possessing a variety of substituents (Me, OMe, Cl, F, and CF(3)) at the ortho-, meta-, or para-positions of the phenyl ring, in conjunction with either a N-bis-(2-propynyl) or a N-mono-(2-propynyl) moiety, were synthesized and compared to the novel neuroprotective drug beta-phenylethylidenehydrazine (PEH) with regard to their ability to inhibit the enzymes GABA-transaminase (GABA-T) and monoamine oxidase (MAO)-A and -B in vitro in brain tissue. Two of the analogs synthesized (mono- and bis-N-propynylPEH) were also studied exvivo in rats to compare their effects to those of PEH with regard to ability to inhibit GABA-T and MAO and to change brain levels of several important amino acids. Unlike PEH, none of the new drugs inhibited GABA-T in vitro at 10 or 100 microM, and all of the drugs (including PEH) were poor inhibitors (at 10 microM) of MAO-A and -B invitro. The two analogs studied exvivo inhibited GABA-T to a lesser extent than PEH, unlike PEH that did not elevate brain levels of GABA, and inhibited MAO-A and -B more potently than PEH. Interestingly, unlike PEH, the two analogs caused marked increases in brain levels of glycine; because of the current interest in drugs that increase glycine availability in the brain as potential antipsychotic drugs, these two analogs now warrant further investigation.


Assuntos
4-Aminobutirato Transaminase/antagonistas & inibidores , Alcinos/química , Encéfalo/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Hidrazinas/farmacologia , Monoaminoxidase/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicina/metabolismo , Hidrazinas/síntese química , Hidrazinas/química , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
6.
Bioorg Med Chem ; 13(14): 4389-95, 2005 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-15927473

RESUMO

Beta-Phenylethylidenehydrazine (PEH) has been demonstrated previously to be an inhibitor of gamma-aminobutyric acid transaminase (GABA-T) and to cause a marked increase in rat brain levels of GABA, a major neurotransmitter. A group of PEH analogs, possessing a variety of substituents (Me, OMe, Cl, F, and CF3) at the 2-, 3-, and 4-positions of the phenyl ring, were synthesized for evaluation as inhibitors of GABA-T. The details of the synthesis and chemical characterization of the analogs are described. Preliminary in vitro screening for GABA-T inhibition showed that all the analogs possessed activity against this enzyme, although substitution of CF3 at the 2- and 4-positions caused reduced activity. One of the drugs, 4-fluoro-beta-phenylethylidenehydrazine, was investigated further ex vivo, where it was shown to inhibit GABA-T, elevate brain levels of GABA, and decrease levels of glutamine, similar to the profile observed previously for PEH.


Assuntos
Hidrazinas/química , Hidrazinas/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Avaliação Pré-Clínica de Medicamentos , Proteínas da Membrana Plasmática de Transporte de GABA , Espectroscopia de Ressonância Magnética , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espectroscopia de Infravermelho com Transformada de Fourier , Ácido gama-Aminobutírico/metabolismo
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