RESUMO
RATIONALE: Gallic acid is one of the most common polyphenols in natural products and human diet. The consumption of gallic acid reduces the incidence of cardiovascular diseases, chronic metabolic disorders and cancers. Most previous publications focused on the antioxidative or prooxidative properties of gallic acid. In the present work, gallic acid as a trapping agent of blood formaldehyde was investigated by liquid chromatography/tandem mass spectrometry (LC/MS/MS) and neutral loss scan. METHODS: Serum samples incubated with gallic acid were subjected to LC/MS/MS analysis using an LTQ XL ion trap mass spectrometer. The adduct ions of gallic acid-formaldehyde-amino acids were explored by investigation of their fragmentation patterns and neutral loss scan experiments. RESULTS: A series of Mannich adducts (namely, gallic acid-formaldehyde-alanine, gallic acid-formaldehyde-proline, gallic acid-formaldehyde-leucine or gallic acid-formaldehyde-isoleucine and gallic acid-formaldehyde-phenylalanine) were identified as metabolites by neutral loss scan experiments. CONCLUSIONS: This work demonstrated that serum amino acids are involved in gallic acid detoxification of formaldehyde. Because excessive formaldehyde in blood is implicated in a variety of disease pathologies, detoxification of formaldehyde, especially endogenous formaldehyde, may be another health beneficial effect of gallic acid. It also suggested that more attention should be paid to Mannich-type metabolites of polyphenol-formaldehyde-amino acids in research into the pharmacokinetics and bioavailability of polyphenols.
Assuntos
Aminoácidos/sangue , Cromatografia Líquida/métodos , Formaldeído/sangue , Ácido Gálico/sangue , Aminoácidos/química , Formaldeído/química , Ácido Gálico/química , Humanos , Estrutura Molecular , Espectrometria de Massas em Tandem/métodosRESUMO
Based on the strategy of molecular hybridization, diketo acid fragment as a classical phamacophore of integrase inhibitors was introduced to reverse transcriptase inhibitors diarylpyrimidines to design a series of diarylpyrimidine-diketo acid hybrids (DAPY-DKAs). The target molecules 10b and 11b showed inhibitory activities against WT HIV-1 with EC50 values of 0.18µM and 0.14µM, respectively. And the results of molecular docking demonstrated the potential binding mode and revealed that the DKA moiety and its ester could both be tolerated in the nonnucleoside binding site (NNBS) of HIV-1 RT.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Pirimidinas/química , Pirimidinas/farmacologia , Fármacos Anti-HIV/síntese química , Linhagem Celular , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Integrase de HIV/metabolismo , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/farmacologia , Humanos , Cetoácidos/síntese química , Cetoácidos/química , Cetoácidos/farmacologia , Simulação de Acoplamento Molecular , Pirimidinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologiaRESUMO
30 new analogues of diarylpyrimidines were synthesized for further structural modifications, involving not only the linker but also the wing α of DAPYs. The anti-HIV-1 activities of all target molecules were evaluated, and most of them exhibited potent anti-HIV-1 (WT) activities and low cytotoxicities. Among which, compound 4g showed excellent activities against WT HIV-1 with an EC50 value of 5.8nM and SI of up to 26,034. Another compound 4ab bearing a novel pyridinyl Wing α also displayed attractive activities. The structure-activity relationship (SAR) study was also summarized.
Assuntos
Fármacos Anti-HIV/farmacologia , HIV-1/efeitos dos fármacos , Pirimidinas/química , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por ElectrosprayRESUMO
Reverse transcriptase (RT) and integrase (IN) are two indispensable enzymes in human immunodeficiency virus type 1 (HIV-1) replication. RT is responsible for the transformation of the single-stranded RNA viral genome into double-stranded DNA, and IN catalyzes the integration of viral DNA into the host DNA. Although highly active antiretroviral therapy (HAART) combining nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) with nonnucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) could suppress successfully HIV viral load and reduce evidently the mortality of HIV infected people, it involves the difficulty of perfect adherence, and other drawbacks such as viral rebound, toxicities and multi-drug resistances. Recently, rational drug design has become a dominant technique for the development of multi-target drugs. And the rationally designed dual inhibitors of HIV-1 RT and IN have become a hot topic of anti-HIV research. In this review, the advances in rationally designed dual inhibitors of HIV-1 RT and IN were summarized, including structurally diverse inhibitors, their structure-activity relationship (SAR) studies as well as binding mode analysis.
Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , Inibidores de Integrase de HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , Integrases/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , HIV/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/síntese química , Inibidores de Integrase de HIV/química , Transcriptase Reversa do HIV/metabolismo , Humanos , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-AtividadeRESUMO
To improve the conformational flexibility and positional adaptability of the traditional diarylpyrimidines (DAPYs), a family of diarylpyrimidines featuring a C-N diatomic linker between the left wing benzene ring and the central pyrimidine was firstly designed, synthesized, and evaluated for in vitro anti-HIV activity. Most of target molecules showed excellent activities against wild-type (WT) HIV-1. Among them the most potent two compounds 12h and 12r displayed extremely potent WT HIV-1 inhibitory activities with an EC50 of 2.6 nM and 3.0 nM, respectively, while their selective index (CC50/EC50) values were both over 1000. Another compound 12b (EC50 14.9 nM) was also noteworthy due to its high SI of 18,614. Moreover, all of compounds were evaluated for their WT HIV-1 reverse transcriptase activities, which shown that the newly synthesized CH2NH-DAPYs bind to HIV-1 RT and belong to the genuine NNRTIs. However, the synthesized compounds lack the activities against HIV-1 double mutant (RES056) and HIV-2 (ROD). Thus it is an upcoming objective to improve the activities against HIV-1 double mutants.
Assuntos
Fármacos Anti-HIV/farmacologia , Desenho de Fármacos , HIV-1/efeitos dos fármacos , HIV-2/efeitos dos fármacos , Pirimidinas/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , HIV-1/genética , HIV-2/genética , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: γ-Aminobutyric acid (GABA) receptors (GABARs) are validated targets of insecticides. Bicyclophosphorothionates are a group of insecticidal compounds that act as noncompetitive antagonists of GABARs. We previously reported that the analogs exhibit various degrees of selectivity for housefly versus rat GABARs, depending on substitutions at the 3- and 4-positions. We here sought to elucidate the unsolved mechanisms of the receptor selectivity using quantitative structure-activity relationship (QSAR), molecular docking, and molecular dynamics approaches. RESULTS: Three-dimensional (3D)-QSAR studies using Topomer comparative molecular field analysis quantitatively demonstrated how the introduction of a small alkyl group at the 3-position of bicyclophosphorothionates contributes to the housefly versus rat GABAR selectivity. To investigate the molecular mechanisms of the selective action, bicyclophosphorothionates were docked into housefly Resistance to dieldrin (RDL) GABAR and rat α1ß2γ2 GABAR homology models built using the published 3D-structures of human GABARs as templates. The results of molecular docking and molecular dynamics simulations revealed that the 2'Ala and 6'Thr residues of the RDL subunit within the channel are the key amino acids for binding to the housefly GABARs, whereas the 2'Ser residue of γ2 subunit plays a crucial role in binding to rat GABARs. CONCLUSION: We revealed the molecular mechanisms underlying the selective antagonistic action of bicyclophosphorothionates on housefly versus rat GABARs. The information presented should help design and develop novel, safe GABAR-targeting insecticides. © 2023 Society of Chemical Industry.
Assuntos
Moscas Domésticas , Inseticidas , Ratos , Animais , Humanos , Receptores de GABA/metabolismo , Inseticidas/química , Moscas Domésticas/metabolismo , Simulação de Acoplamento Molecular , Antagonistas GABAérgicos/químicaRESUMO
Invertebrate γ-aminobutyric acid (GABA)-gated chloride channels (GABACls) and glutamate-gated chloride channels (GluCls), which function as inhibitory neurotransmitter receptors, are important targets of insecticides and antiparasitic agents. The antagonism of GABACls and GluCls by 4-isobutyl-3-isopropylbicyclophosphorothionate (PS-14) was examined in cultured cockroach and rat neurons using a whole-cell patch-clamp method. The results indicated that PS-14 selectively blocks cockroach GABACls relative to cockroach GluCls and rat GABACls. PS-14 represents a useful probe for the study of insect GABA receptors.
Assuntos
Canais de Cloreto/antagonistas & inibidores , Baratas/metabolismo , Insetos/metabolismo , Inseticidas/química , Fosfatos/química , Animais , Células Cultivadas , Canais de Cloreto/metabolismo , Baratas/efeitos dos fármacos , Inseticidas/síntese química , Inseticidas/toxicidade , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Técnicas de Patch-Clamp , Fosfatos/metabolismo , Fosfatos/toxicidade , Ligação Proteica , Ratos , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/químicaRESUMO
Salidroside is a phenolic secondary metabolite present in plants of the genus Rhodiola, and studies investigating its extensive pharmacological activities and mechanisms have recently attracted increasing attention. This review summarizes the progress of recent research on the antiproliferative activities of salidroside and its effects on breast, ovarian, cervical, colorectal, lung, liver, gastric, bladder, renal, and skin cancer as well as gliomas and fibrosarcomas. Thus, it provides a reference for the further development and utilization of salidroside.
Assuntos
Rhodiola , Glucosídeos/farmacologia , Fígado , Fenóis/farmacologiaRESUMO
OBJECTIVE: We investigated the antitumor effects of salidroside and preliminarily examined its underlying mechanisms by establishing a nude mouse model bearing MCF-7 breast cancer cell xenografts. METHODS: The mice were grouped and intraperitoneally injected with salidroside, paclitaxel, or physiological saline. Tumor samples were weighed, and immunohistochemical staining with hematoxylin and eosin and anti-CD34 antibody was performed. Tumor cell apoptosis was observed using the terminal deoxynucleotidyl transferase deoxyuridine dUTP nick end labeling assay. Bcl-1, p53, Bax, and caspase 3 expression in tumor tissues was determined via western blotting. RESULTS: The tumor inhibition rate of high-dose salidroside was 75.16%, which was significantly higher than the rates for paclitaxel and saline. A tumor tissue pathology analysis revealed that high-dose salidroside inhibited tumor cell proliferation and promoted tumor cell apoptosis. Western blotting revealed that Bcl-2 and p53 expression were significantly lower in the salidroside group than in the other groups, whereas Bax and caspase 3 (17 kDa) expression were increased. CONCLUSIONS: Salidroside was more effective than paclitaxel in inhibiting tumor growth in MCF-7 breast cancer cell-bearing nude mice. The mechanism of action may involve Bcl-2 and p53 downregulation and Bax and caspase 3 upregulation, thereby increasing proapoptotic factor expression and inducing tumor cell apoptosis.
Assuntos
Neoplasias da Mama/patologia , Glucosídeos/farmacologia , Fenóis/farmacologia , Animais , Apoptose , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Marcação In Situ das Extremidades Cortadas , Células MCF-7 , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteínas Proto-Oncogênicas c-bcl-2/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) have been playing an important role in the fight against acquired immunodeficiency syndrome (AIDS). Diarylpyrimidines (DAPYs) as the second generation NNRTIs, represented by etravirine (TMC125) and rilpivirine (TMC278), have attracted extensive attention due to their extraordinary potency, high specificity and low toxicity. However, the rapid emergence of drug-resistant virus strains and dissatisfactory pharmacokinetics of DAPYs present new challenges. In the past two decades, an increasing number of novel DAPY derivatives have emerged, which significantly enriched the structure-activity relationship of DAPYs. Studies of crystallography and molecular modeling have afforded a lot of useful information on structural requirements of NNRTIs, which contributes greatly to the improvement of their resistance profiles. In this review, we reviewed the discovery history and their evolution of DAPYs including their structural modification, derivatization and scaffold hopping in continuous pursuit of excellent anti-HIV drugs. And also, we discussed the prospect of DAPYs and the directions of future efforts.
Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Pirimidinas/química , Pirimidinas/farmacologia , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Relação Estrutura-AtividadeRESUMO
A number of widely diverse compounds that show inhibitory activities at the picrotoxinin binding sites in housefly and rat GABA receptors were investigated by using the distance comparison technique (DISCOtech) and comparative molecular field analysis (CoMFA) methods to explore the pharmacophore models and the three-dimensional quantitative structure-activity relationships (3D-QSAR) of the compounds. These compounds consist of three diverse types of noncompetitive GABA receptor antagonists, i.e., trioxabicyclooctanes and their derivatives, picrodendrins and related terpenoids, and fipronil and its analogs. For investigation of the structural requirements for inhibitory activity at the picrotoxinin binding site of GABA receptor, DISCOtech pharmacophore models containing one center of hydrophobic ring and two hydrogen bond acceptor atoms for both housefly-head and rat-brain GABA receptors were constructed, respectively. In particular, the interacting areas in housefly receptors appear to be wider than that in rat receptors, the differences between rat and housefly receptor models implicate the selectivity of noncompetitive GABA receptor antagonists. In addition, corresponding CoMFA models with good statistical indices (r(2)>0.9 and q(2)>0.5) were also obtained. These models can be used as guidance for the development of new compounds with high activities and selectivities.
Assuntos
Antagonistas GABAérgicos/química , Modelos Moleculares , Picrotoxina/análogos & derivados , Receptores de GABA/química , Animais , Sítios de Ligação , Moscas Domésticas , Estrutura Molecular , Picrotoxina/química , Relação Quantitativa Estrutura-Atividade , Ratos , SesterterpenosRESUMO
OBJECTIVE: To optimize the extraction process of baicalin from Scutellaria Baicalensis Georgi with ethanol. METHODS: The extraction process of baicalin from Scutellaria Baicalensis Georgi was optimized with the aid of orthogonal experiments. RESULTS: The optimal parameters were obtained as follows: extracting temperature, extracting time, ethanol concentration and mechanical stirring speed were 80 degrees C, 1 h, 60% and 400 r/min, respectively. The extracting rate of baicalin was 83.90%. CONCLUSION: Comparing ethanol circumfluence, boiling water, ultrasonic wave and semi-bionic on extracting baicalin from Scutellaria baicalensis Georgi, the ethanol circumfluence extraction is better than other technological conditions on extracting baicalin.
Assuntos
Flavonoides/isolamento & purificação , Extratos Vegetais/química , Scutellaria baicalensis/química , Medicamentos de Ervas Chinesas , EtanolRESUMO
Glyphosate is a non-selective herbicide which acts by inhibiting 5-enolpyruvylshikimate-3-phosphate synthase. Wheat cytochrome P450 monooxygenase specifically catalyzes the metabolism of some sulfonylurea herbicides such as chlorsulfuron and triasulfuron. Here we report that glyphosate is an inhibitor of a wheat cytochrome (CYP71C6v1), the cDNA of which was amplified by RT-PCR and heterologously expressed in yeast. The microsomal fractions derived from this strain had a Soret peak at 502 nm in the reduced carbon monoxide difference spectrum, which is a typical spectral characteristic. The addition of glyphosate to the microsomal protein resulted in a Type II spectrum indicative of binding via the nitrogen group to haem of cytochrome P450 as a sixth ligand. A spectral dissociation constant, K(s) of 70 micromol litre(-1) was observed and an IC50 of 11 micromol litre(-1) was found for glyphosate inhibition of CYP71C6v1 P450 activity.
Assuntos
Inibidores das Enzimas do Citocromo P-450 , Glicina/análogos & derivados , Glicina/farmacologia , Herbicidas/farmacologia , Triticum/enzimologia , Sequência de Aminoácidos , Sequência de Bases , Sistema Enzimático do Citocromo P-450/genética , Sistema Enzimático do Citocromo P-450/metabolismo , Expressão Gênica , Dados de Sequência Molecular , Organismos Geneticamente Modificados , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Saccharomyces cerevisiae/genética , Triticum/genética , GlifosatoRESUMO
A series of novel enaminone amides with improved side effect were synthesized by Hogenkamp et al. To explore the action mechanisms of enaminone amides, the homology model of rat alpha1beta2gamma2 GABAR was generated using the cryo-electron microscopy structure of the nAChR of Torpedo marmorata and the AChBP of Lymnaea stagnalis as the templates. Molecular docking and pharmacophore analyses allowed us to speculate the critical residues involving to the recognition of the ligands. The docking results indicated His128, Tyr186 and Tyr236 of alpha subunit were essential to form H-bond interactions contacts with the ligands. Specially, the N-substituents of enaminone amides as the sterically favored areas could form the important hydrophobic interactions with the residue Tyr186.
Assuntos
Amidas/química , Amidas/metabolismo , Modelos Moleculares , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Homologia de Sequência de Aminoácidos , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Ligação de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Dados de Sequência Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Ratos , Receptores Nicotínicos/química , TorpedoRESUMO
For better understanding of the mechanisms of selective binding of the representative nicotinic acetylcholine receptor (nAChR) agonist neonicotinoid Imidacloprid (IMI), three-dimensional models of fruit fly alpha 1 beta 2 and rat alpha 4beta 2 nAChRs were generated by homology modeling, using the crystal structure of the acetylcholine-binding protein (AChBP) of Lymnaea stagnalis and the nAChR of mus musculus as the templates, respectively. The conformational stability of the two models was studied by molecular dynamics (MD) and the quality of the models was confirmed. Especially, insecticide Imidacloprid was docked into the putative binding site of the fruit fly alpha 1 beta 2 and rat alpha 4 beta 2 nAChRs by Surflex-docking. The calculated docking energies were in agreement with the experimental data and the putative binding sites were also consistent with the results from labeling and mutagenesis experiments. Furthermore, the mechanisms of Imidacloprid selectively acting on fruit fly versus rat nAChRs were discussed.
Assuntos
Imidazóis/metabolismo , Inseticidas/metabolismo , Agonistas Nicotínicos/metabolismo , Nitrocompostos/metabolismo , Receptores Nicotínicos/metabolismo , Acetilcolina/genética , Acetilcolina/metabolismo , Animais , Sítios de Ligação/genética , Drosophila/genética , Drosophila/metabolismo , Imidazóis/química , Imidazóis/farmacologia , Inseticidas/química , Inseticidas/farmacologia , Lymnaea/genética , Lymnaea/metabolismo , Camundongos , Conformação Molecular , Simulação de Dinâmica Molecular , Neonicotinoides , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Nitrocompostos/química , Nitrocompostos/farmacologia , Ligação Proteica/genética , Ratos , Receptores Nicotínicos/química , Receptores Nicotínicos/genéticaRESUMO
To explore the three-dimensional quantitative structure-activity relationships (3D-QSAR) and the pharmacophore model of a new class of potent activators of the anthranilic diamide ryanodine receptor (RyR), comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and distance comparison technique (DISCOtech) were performed on 38 anthranilic diamides. Successful CoMFA and CoMSIA models yielded "leave-one-out" (LOO) cross-validated correlation coefficient (q(2)) values of 0.785 and 0.788 and non-cross-validated correlation coefficient (r(2)) values of 0.958 and 0.981, respectively. Results were graphically interpreted in terms of field contribution maps. A DISCOtech pharmacophore model containing an aromatic ring center, a hydrophobic ring center, a hydrogen bond-donor and a hydrogen bond-acceptor was constructed. This model indicated that hydrophobic interaction and hydrogen bonds have important roles in the interactions between activators and RyRs, which was consistent with CoMSIA results. The information obtained from CoMFA, CoMSIA and DISCOtech models enabled interpretation of the structure-activity relationships of anthranilic diamides. Based on the constructed models, some vital features for the interaction of anthranilic diamides with RyRs were identified, which may prove helpful in designing more potent RyR activators.
Assuntos
Inseticidas/química , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Canal de Liberação de Cálcio do Receptor de Rianodina/química , ortoaminobenzoatos/química , Agonistas dos Canais de Cálcio/químicaRESUMO
BACKGROUND: Bicyclophosphorothionates (2,6,7-trioxa-1-phosphabicyclo[2.2.2]octane-1-sulfides) are blockers (or non-competitive antagonists) of gamma-aminobutyric acid (GABA) receptor channels. Twenty-two bicyclophosphorothionates with different 3- and 4-substituents were synthesised, and [(3)H]4'-ethynyl-4-n-propylbicycloorthobenzoate (EBOB) binding assays were performed to evaluate their affinities for housefly and rat GABA receptors. RESULTS: Introduction of an isopropyl group at the 3-position enhanced the affinity of bicyclophosphorothionates for housefly GABA receptors and reduced the affinity towards rat GABA receptors. The 4-isopentyl-3-isopropylbicyclophosphorothionate showed the highest affinity for housefly GABA receptors (IC(50) = 103 nM) among the analogues tested, while the 4-cyclohexylbicyclophosphorothionate showed the highest affinity for rat GABA receptors (IC(50) = 125 nM). Among the bicyclophosphorothionates synthesised to date, the former analogue exhibited the highest selectivity for housefly GABA receptors, with an IC(50)(rat)/IC(50)(fly) ratio of approximately 97. Three-dimensional GABA receptor models successfully explained the structure-activity relationships of the bicyclophosphorothionates. CONCLUSION: The results indicate that minor structural modifications of blockers can change their selectivity for insect versus mammalian GABA receptors. The substituent at the 3-position of the bicyclophosphorothionates dictates selectivity for housefly versus rat GABA receptors. This information should prove useful for the design of safer insecticides and parasiticides.
Assuntos
Antagonistas GABAérgicos/química , Antagonistas GABAérgicos/farmacologia , Moscas Domésticas/efeitos dos fármacos , Moscas Domésticas/metabolismo , Fosfitos/química , Fosfitos/farmacologia , Receptores de GABA/metabolismo , Sequência de Aminoácidos , Animais , Compostos Bicíclicos Heterocíclicos com Pontes/metabolismo , Fenômenos Eletrofisiológicos/efeitos dos fármacos , Antagonistas GABAérgicos/síntese química , Antagonistas GABAérgicos/metabolismo , Moscas Domésticas/fisiologia , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Neurônios/citologia , Neurônios/efeitos dos fármacos , Fosfitos/síntese química , Fosfitos/metabolismo , Conformação Proteica , Ratos , Receptores de GABA/química , Relação Estrutura-Atividade , Especificidade por SubstratoRESUMO
For better understanding of the molecular interactions of inhibitors with CYP450 1A1, a series of benzoxazoles and benzothiazoles were analyzed by comparative molecular field analysis (CoMFA) and molecular docking. Two conformer-based alignment strategies were employed to construct reliable CoMFA models. The best CoMFA model yielded a predictive correlation coefficient r(2)(pred) value of 0.809. Furthermore, a three-dimensional model of CYP450 1A1 was generated by homology modeling using CYP450 1A2 as a template, and docking of 48 CYP450 1A1 inhibitors into the putative binding sites of the CYP450 1A1 were studied. The results obtained from this study will be helpful in the design of potentially active CYP450 1A1 inhibitors.
Assuntos
Benzotiazóis/química , Benzoxazóis/química , Simulação por Computador , Citocromo P-450 CYP1A1/antagonistas & inibidores , Inibidores Enzimáticos/química , Benzotiazóis/síntese química , Benzotiazóis/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Sítios de Ligação , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Modelos Moleculares , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade , Eletricidade EstáticaRESUMO
To further explore the mechanism of selective binding of the representative gamma-aminobutyric acid receptors (GABARs) noncompetitive antagonist (NCA) fipronil to insect over mammalian GABARs, three-dimensional models of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABAR were generated by homology modeling, using the cryo-electron microscopy structure of the nicotinic acetylcholine receptor (nAChR) of Torpedo marmorata as a template. Fipronil was docked into the putative binding site of the human alpha 1 beta 2 gamma 2 and house fly beta 3 receptors by Surflex-docking, and the calculated docking energies are in agreement with experimental results. The GABA receptor antagonist fipronil exhibited higher potency with house fly beta 3 GABAR than with human alpha 1 beta 2 gamma 2 GABAR. Furthermore, analyses of Surflex-docking suggest that the H-bond interaction of fipronil with Ala2 and Thr6 in the second transmembrane segment (TM2) of these GABARs plays a relatively important role in ligand selective binding. The different subunit assemblies of human alpha 1 beta 2 gamma 2 and house fly beta 3 GABARs may result in differential selectivity for fipronil.