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1.
Phys Chem Chem Phys ; 21(36): 19795-19804, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31482888

RESUMO

Allostery plays important roles in the regulation of many biological processes, such as signal transduction and transcriptional regulation. Although great advances have been achieved in understanding the allosteric mechanism through experimental and theoretical investigations, the details of the allosteric process are still not clear. Here, using the N-terminal domain of calmodulin (nCaM) as the model protein, we reported the atomic level characterization of the allosteric process induced by Ca2+ binding through extensive and unbiased molecular dynamics simulations. In two trajectories, it was found that Ca2+ first binds to EF-hand 2 and then induces the conformational transformation of nCaM from the Apo to Holo state assisted by second Ca2+ binding to EF-hand 1 completely. The binding order was consistent with a recent experimental result. The simulations also indicated that the two EF-hands changed conformations synergistically and the EF-hand 2 showed an earlier and more gradual conformational transition. Meanwhile, the allosteric process of nCaM triggered by Ca2+ binding might be completed within hundreds of nanoseconds in a two-state-like manner. This was validated by biased simulations, in which the Ca2+ ions were restrained near the binding sites. This work provides the molecular details of the conformational transition of nCaM triggered by Ca2+ binding.


Assuntos
Cálcio/química , Calmodulina/química , Íons/química , Simulação de Acoplamento Molecular , Domínios Proteicos , Ligação Proteica , Conformação Proteica
3.
Pestic Biochem Physiol ; 159: 91-97, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400790

RESUMO

The organophosphorus pesticide, triazophos (TAP) was banned to use in agriculture in several countries due to its high toxicity. However, TAP was still widely used and frequently detected in foods. Recently, many studies reported the endocrine-disrupting effect of pesticides, especially the hypothalamic-pituitary-thyroid and hypothalamic-pituitary-gonadal axis. In this study, adult male Wistar rats were exposed to TAP at the dose of 0.164 and 1.64 mg/kg bodyweight (~1/500th and 1/50th of LD50) for 24 weeks and serum contents of hormones were measured. TAP exposure significantly reduced serum contents of adrenocorticotropic hormone, corticosterone and epinephrine in rats (p < .05), leading to the delay in glucose homeostasis during the insulin tolerance test and decrease in serum contents of total cholesterol, triglyceride and low density lipoprotein. Molecular docking results suggested TAP may be an antagonist of glucocorticoid receptor which decreased significantly in the liver of rats, resulting in the decreased expression of 11ß-hydroxysteroid dehydrogenase 1 and PEPCK1. This study revealed that TAP is a potential endocrine disruptor, especially in the hypothalamus-pituitary-adrenal system and may disturb the metabolism by affecting glucocorticoid receptor. This study provided new evidence about the toxicity of TAP and it was necessary to strictly control the usage of TAP in food.


Assuntos
Hipotálamo/efeitos dos fármacos , Organotiofosfatos/farmacologia , Praguicidas/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Triazóis/farmacologia , 11-beta-Hidroxiesteroide Desidrogenases/metabolismo , Animais , Colesterol/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Simulação de Acoplamento Molecular , Ratos , Ratos Wistar , Triglicerídeos/metabolismo
4.
Phys Chem Chem Phys ; 21(32): 17821-17835, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31373340

RESUMO

The rise of New Delhi metallo-beta-lactamase-1 (NDM-1) producers is a major public health concern due to carbapenem resistance. Infections caused by carbapenem-resistant enterobacteria (CRE) are classified as a serious problem. To understand the structure and function of NDM-1, an amino acid replacement approach is considered as one of the methods to get structural insight. Therefore, we have generated novel mutations (N193A, S217A, G219A and T262A) near active sites and an omega-like loop to study the role of conserved residues of NDM-1. The minimum inhibitory concentrations (MICs) of ampicillin, imipenem, meropenem, cefotaxime, cefoxitin and ceftazidime for all mutants were found to be reduced 2 to 6 fold, compared to a wild type NDM-1 producing strain. The Km values increased while Kcat and Kcat/Km values were decreased compared to wild type. The affinity as well as the catalysis properties of these mutants were reduced considerably for imipenem, meropenem, cefotaxime, cefoxitin, and ceftazidimem compared to wild type, hence the catalytic efficiencies (Kcat/Km) of all mutant enzymes were reduced owing to the poor affinity of the enzyme. The IC50 values of these mutants with respect to each drug were reduced compared to wild type NDM-1. MD simulations and docking results from the mutant protein models, along with the wild type example, showed stable and consistent RMSD, RMSF and Rg behavior. The α-helix content values of all mutant proteins were reduced by 13%, 6%, 14% and 9% compared to NDM-1. Hence, this study revealed the impact role of active sites near residues on the enzyme catalytic activity of NDM-1.


Assuntos
Antibacterianos/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , beta-Lactamases/química , Antibacterianos/farmacologia , Biocatálise , Domínio Catalítico , Farmacorresistência Bacteriana , Cinética , Testes de Sensibilidade Microbiana , Mutagênese Sítio-Dirigida , Mutação , Ligação Proteica , Estrutura Secundária de Proteína , Termodinâmica , beta-Lactamases/genética , beta-Lactamases/metabolismo
5.
Pestic Biochem Physiol ; 158: 156-165, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31378352

RESUMO

Culex pipiens is a main vector for Bancroftian filariasis, Rift Valley Fever and diseases caused by other viruses, leaving several peoples with disabilities. In recent years, plant derived compounds have received much attention as potential alternatives to synthetic chemicals due to their low toxicity to mammals and environmental persistence. Twenty-one monoterpenes from different chemical groups (hydrocarbons and oxygenated products) were evaluated against Culex pipiens larvae. In addition, in vivo biochemical studies including effects on acetylcholine esterase (AChE), acid and alkaline phosphatases (ACP and ALP), total adenosine triphosphatase (ATPase) and gamma-aminobutyric acid transaminase (GABA-T) were investigated. Furthermore, in silico studies including pharmacophore elucidation, ADMET analysis and molecular docking of these compounds were performed. Among all tested monoterpenes, hydrocarbons [p-cymene, (R)-(+)-limonene and (+)-α-pinene], acetates (cinnamyl acetate, citronellyl acetate, eugenyl acetate and terpinyl acetate), alcohols [(±)-ß-citronellol and terpineol], aldehydes [citral and (1R)-(-)-myrtenal] and ketone [(R)-(+)-pulegone] exhibited the highest larval toxicity with LC50 = 14.88, 27.97, 26.13, 2.62, 3.81, 2.74, 21.65, 1.64, 21.70, 21.76, 1.68 and 1.90 mg/L after 48 h of exposure, respectively. The compounds proved a significant inhibition of all tested enzymes except total ATPase. The biochemical and molecular docking studies proved that AChE and GABA-T were the main targets for the tested monoterpenes.


Assuntos
Culex/virologia , Inseticidas/farmacologia , Monoterpenos/farmacologia , Fosfatase Alcalina/metabolismo , Animais , Culex/patogenicidade , Filariose Linfática/transmissão , Ativação Enzimática/efeitos dos fármacos , Esterases/metabolismo , Simulação de Acoplamento Molecular , Transaminases/metabolismo
6.
Chem Commun (Camb) ; 55(69): 10214-10217, 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31380528

RESUMO

The l,d-transpeptidases (Ldts) are promising antibiotic targets for treating tuberculosis. We report screening of cysteine-reactive inhibitors against LdtMt2 from Mycobacterium tuberculosis. Structural studies on LdtMt2 with potent inhibitor ebselen reveal opening of the benzisoselenazolone ring by a nucleophilic cysteine, forming a complex involving extensive hydrophobic interactions with a substrate-binding loop.


Assuntos
Azóis/química , Azóis/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Mycobacterium tuberculosis/enzimologia , Compostos Organosselênicos/química , Compostos Organosselênicos/farmacologia , Peptidil Transferases/antagonistas & inibidores , Antituberculosos/química , Antituberculosos/farmacologia , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Cisteína/metabolismo , Humanos , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Peptidil Transferases/metabolismo , Tuberculose/tratamento farmacológico , Tuberculose/microbiologia
7.
J Agric Food Chem ; 67(33): 9210-9219, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31390203

RESUMO

The insecticidal and antifeedant activities of five 7-chloro-4-(1H-1,2,3-triazol-1-yl)quinoline derivatives were evaluated against the maize armyworm, Spodoptera frugiperda (J.E. Smith). These hybrids were prepared through a copper-catalyzed azide alkyne cycloaddition (CuAAC, known as a click reaction) and displayed larvicidal properties with LD50 values below 3 mg/g insect, and triazolyl-quinoline hybrid 6 showed an LD50 of 0.65 mg/g insect, making it 2-fold less potent than methomyl, which was used as a reference insecticide (LD50 = 0.34 mg/g insect). Compound 4 was the most active antifeedant derivative (CE50 = 162.1 µg/mL) with a good antifeedant index (56-79%) at concentrations of 250-1000 µg/mL. Additionally, triazolyl-quinoline hybrids 4-8 exhibited weak inhibitory activity against commercial acetylcholinesterase from Electrophorus electricus (electric-eel AChE) (IC50 = 27.7 µg/mL) as well as low anti-ChE activity on S. frugiperda larvae homogenate (IC50 = 68.4 µg/mL). Finally, molecular docking simulations suggested that hybrid 7 binds to the catalytic active site (CAS) of this enzyme and around the rim of the enzyme cavity, acting as a mixed (competitive and noncompetitive) inhibitor like methomyl. Triazolyl-quinolines 4-6 and 8 inhibit AChE by binding over the perimeter of the enzyme cavity, functioning as noncompetitive inhibitors. The results described in this work can help to identify lead triazole structures from click chemistry for the development of insecticide and deterrent products against S. frugiperda and related insect pests.


Assuntos
Inseticidas/síntese química , Inseticidas/farmacologia , Larva/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Spodoptera/efeitos dos fármacos , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Animais , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Química Click , Simulação por Computador , Proteínas de Insetos/antagonistas & inibidores , Proteínas de Insetos/química , Proteínas de Insetos/metabolismo , Inseticidas/química , Larva/enzimologia , Larva/crescimento & desenvolvimento , Simulação de Acoplamento Molecular , Doenças das Plantas/parasitologia , Spodoptera/enzimologia , Spodoptera/crescimento & desenvolvimento , Zea mays/parasitologia
8.
J Chem Theory Comput ; 15(9): 5135-5143, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31390206

RESUMO

Predicting the assembly of multiple proteins into specific complexes is critical to understanding their biological function in an organism and thus the design of drugs to address their malfunction. Proteins are flexible molecules, which inherently pose a problem to any protein docking computational method, where even a simple rearrangement of the side chain and backbone atoms at the interface of binding partners complicates the successful determination of the correct docked pose. Herein, we present a means of representing protein surface, electrostatics, and local dynamics within a single volumetric descriptor. We show that our representations can be physically related to the surface-accessible solvent area and mass of the protein. We then demonstrate that the application of this representation into a protein-protein docking scenario bypasses the need to compensate for, and predict, specific side chain packing at the interface of binding partners. This representation is leveraged in our de novo protein docking software, JabberDock, which can accurately and robustly predict difficult target complexes with an average success rate of >54%, which is comparable to or greater than the currently available methods.


Assuntos
Simulação de Acoplamento Molecular , Proteínas/química , Eletricidade Estática , Termodinâmica , Ligação Proteica , Propriedades de Superfície
9.
J Agric Food Chem ; 67(37): 10521-10533, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31461284

RESUMO

This work was designed to comparatively investigate 27 dietary flavonoids that act as α-glucosidase inhibitors and insulin sensitizers. On the basis of the results of an in vitro experiment of α-glucosidase inhibition, myricetin (IC50 = 11.63 ± 0.36 µM) possessed the strongest inhibitory effect, followed by apigenin-7-O-glucoside (IC50 = 22.80 ± 0.24 µM) and fisetin (IC50 = 46.39 ± 0.34 µM). A three-dimensional quantitative structure-activity relationship model of α-glucosidase inhibitors with good predictive capability [comparative molecular field analysis, q2 = 0.529, optimum number of components (ONC) = 10, R2 = 0.996, F = 250.843, standard error of estimation (SEE) = 0.064, and two descriptors; comparative similarity index analysis, q2 = 0.515, ONC = 10, R2 = 0.997, F = 348.301, SEE = 0.054, and four descriptors] was established and indicated that meta positions of ring B favored bulky and minor, electron-withdrawing, and hydrogen bond donor groups. The presence of electron-donating and hydrogen bond acceptor groups at position 4' of ring B could improve α-glucosidase activity. Position 3 of ring C favored minor, electron-donating, and hydrogen bond donor groups, whereas position 7 of ring A favored bulky and hydrogen bond acceptor groups. Molecular docking screened five flavonoids (baicalein, isorhamnetin-3-O-rutinoside, apigenin-7-O-glucoside, kaempferol-7-O-ß-glucoside, and cyanidin-3-O-glucoside) that can act as insulin sensitizers and form strong combinations with four key protein targets involved in the insulin signaling pathway. Apigenin-7-O-glucoside (60 µM) can effectively improve insulin resistance, and glucose uptake increased by approximately 73.06% relative to the model group of insulin-resistant HepG2 cells. Therefore, apigenin-7-O-glucoside might serve as the most effective α-glucosidase inhibitor and insulin sensitizer. This work may guide diabetes patients to improve their condition through dietary therapy.


Assuntos
Flavonoides/química , Inibidores de Glicosídeo Hidrolases/química , Insulina/metabolismo , Flavonoides/metabolismo , Flavonoides/farmacologia , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Células Hep G2 , Humanos , Simulação de Acoplamento Molecular , Saccharomyces cerevisiae/enzimologia , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/metabolismo , alfa-Glucosidases/química , alfa-Glucosidases/metabolismo
10.
J Enzyme Inhib Med Chem ; 34(1): 1426-1438, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401883

RESUMO

Anaplastic lymphoma kinase (ALK) has been recognised as a promising molecular target of targeted therapy for NSCLC. We performed SAR study of pyrazolo[3,4-b]pyridines to override crizotinib resistance caused by ALK-L1196M mutation and identified a novel and potent L1196M inhibitor, 10g. 10g displayed exceptional enzymatic activities (<0.5 nM of IC50) against ALK-L1196M as well as against ALK-wt. In addition, 10g is an extremely potent inhibitor of ROS1 (<0.5 nM of IC50) and displays excellent selectivity over c-Met. Moreover, 10g strongly suppresses proliferation of ALK-L1196M-Ba/F3 and H2228 cells harbouring EML4-ALK via apoptosis and the ALK signalling blockade. The results of molecular docking studies reveal that, in contrast to crizotinib, 10g engages in a favourable interaction with M1196 in the kinase domain of ALK-L1196M and hydrogen bonding with K1150 and E1210. This SAR study has provided a useful insight into the design of novel and potent inhibitors against ALK gatekeeper mutant.


Assuntos
Quinase do Linfoma Anaplásico/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Quinase do Linfoma Anaplásico/metabolismo , Apoptose/efeitos dos fármacos , Espectroscopia de Ressonância Magnética Nuclear de Carbono-13 , Linhagem Celular Transformada , Proliferação de Células/efeitos dos fármacos , Cromatografia Líquida , Cristalografia por Raios X , Inibidores Enzimáticos/química , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Pirazóis/química , Piridinas/química , Transdução de Sinais/efeitos dos fármacos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
11.
J Enzyme Inhib Med Chem ; 34(1): 1400-1413, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31401897

RESUMO

A large library of derivatives based on the scaffold of 2-(benzylsulfinyl)benzoic acid were synthesised and tested as atypical inhibitors against four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). The exploration of the chemical space around the main functional groups led to the discovery of selective hCA IX inhibitors in the micromolar/nanomolar range, thus establishing robust structure-activity relationships within this versatile scaffold. HPLC separation of some selected chiral compounds and biological evaluation of the corresponding enantiomers was performed along with molecular modelling studies on the most active derivatives.


Assuntos
Ácido Benzoico/química , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Anidrases Carbônicas/efeitos dos fármacos , Desenho de Drogas , Isoenzimas/efeitos dos fármacos , Inibidores da Anidrase Carbônica/síntese química , Domínio Catalítico , Cromatografia Líquida de Alta Pressão , Humanos , Simulação de Acoplamento Molecular , Estereoisomerismo , Relação Estrutura-Atividade
12.
J Enzyme Inhib Med Chem ; 34(1): 1451-1456, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31409143

RESUMO

Herein, we report the effect of nine FDA approved protease inhibitor drugs against a new HIV-1 subtype C mutant protease, E35D↑G↑S. The mutant has five mutations, E35D, two insertions, position 36 (G and S), and D60E. Kinetics, inhibition constants, vitality, Gibbs free binding energies are reported. The variant showed a decreased affinity for substrate and low catalytic efficiency compared to the wild type. There was a significant decrease in the binding of seven FDA approved protease inhibitors against the mutant (p < .0001). Amprenavir and ritonavir showed the least decrease, but still significant reduced activity in comparison to the wildtype (4 and 5 folds, respectively, p = .0021 and .003, respectively). Nelfinavir and atazanavir were the worst inhibitors against the variant as seen from the IC50, with values of 1401 ± 3.0 and 685 ± 3.0 nM, respectively. Thermodynamics data showed less favourable Gibbs free binding energies for the protease inhibitors to the mutant.


Assuntos
Inibidores da Protease de HIV/farmacologia , Protease de HIV/efeitos dos fármacos , HIV-1/enzimologia , Termodinâmica , Protease de HIV/genética , Protease de HIV/metabolismo , Inibidores da Protease de HIV/química , Concentração Inibidora 50 , Cinética , Simulação de Acoplamento Molecular , Mutação
13.
J Chem Theory Comput ; 15(8): 4602-4614, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31268700

RESUMO

Many biological processes are based on molecular recognition between highly charged molecules such as nucleic acids, inorganic ions, charged amino acids, etc. For such cases, it has been demonstrated that molecular simulations with fixed partial charges often fail to achieve experimental accuracy. Although incorporation of more advanced electrostatic models (such as multipoles, mutual polarization, etc.) can significantly improve simulation accuracy, it increases computational expense by a factor of 5-20×. Indirect free energy (IFE) methods can mitigate this cost by modeling intermediate states at fixed-charge resolution. For example, an efficient "reference" model such as a pairwise Amber, CHARMM, or OPLS-AA force field can be used to derive an initial estimate, followed by thermodynamic corrections to a more advanced "target" potential such as the polarizable AMOEBA model. Unfortunately, all currently described IFE methods encounter difficulties reweighting more than ∼50 atoms between resolutions due to extensive scaling of both the magnitude of the thermodynamic corrections and their statistical uncertainty. We present an approach called "simultaneous bookending" (SB) that is fundamentally different from existing IFE methods based on a tunable sampling approximation, which permits scaling to thousands of atoms. SB is demonstrated on the relative binding affinity of Mg2+/Ca2+ to a set of metalloproteins with up to 2972 atoms, finding no statistically significant difference between direct AMOEBA results and those from correcting Amber to AMOEBA. The ability to change the resolution of thousands of atoms during reweighting suggests the approach may be applicable in the future to protein-protein binding affinities or nucleic acid thermodynamics.


Assuntos
Cálcio/metabolismo , Cátions Bivalentes/metabolismo , Magnésio/metabolismo , Metaloproteínas/metabolismo , Animais , Cálcio/química , Cátions Bivalentes/química , Bases de Dados de Proteínas , Humanos , Magnésio/química , Metaloproteínas/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Software , Eletricidade Estática , Termodinâmica
14.
J Enzyme Inhib Med Chem ; 34(1): 1186-1192, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31282228

RESUMO

A series of sixteen benzenesulfonamide derivatives has been synthesised and tested as inhibitors of Vibrio cholerae carbonic anhydrase (CA) enzymes, belonging to α-CA, ß-CA, and γ-CA classes (VchCAα, VchCAß, and VchCAγ). The determined Ki values were compared to those of selected human CA isoforms (hCA I and hCA II). Structure-affinity relationship analysis highlighted that all tested compounds proved to be active inhibitors of VchCAα at nanomolar concentration. The VchCAß activity was lower to respect inhibitory efficacy toward VchCAα, whereas, these benzenesulfonamide derivatives failed to inhibit VchCAγ. Interestingly, compound 7e combined the best activity toward VchCAα and VchCAß. In order to obtain a model for binding mode of our inhibitors toward bacterial CAs, we carried out docking simulations by using the available crystal structures of VchCAß.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Cólera/tratamento farmacológico , Isoenzimas/antagonistas & inibidores , Sulfonamidas/uso terapêutico , Inibidores da Anidrase Carbônica/química , Cólera/enzimologia , Humanos , Interações Hidrofóbicas e Hidrofílicas , Simulação de Acoplamento Molecular , Relação Estrutura-Atividade , Sulfonamidas/química , Vibrio cholerae/enzimologia
15.
J Enzyme Inhib Med Chem ; 34(1): 1247-1258, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31286782

RESUMO

A series of N1,N3-bis (1-oxopropan-2-yl) isophthalamide-based derivatives 4-16 were prepared and their structures were confirmed by different spectral tools. The cytotoxic potentiality of novel compounds 4-16 was assessed by the MTT assay method on colon, lung and breast tumour cell lines. Compound 5 gave the most significant specificity anticancer activity with safety response on normal cell lines. In vitro enzyme assay and several apoptotic parameters were examined to elucidate the mode of action of compound 5. Molecular docking studies also were simulated to put insight and give better understanding to its structural features.


Assuntos
Aminoácidos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , Relação Estrutura-Atividade
16.
J Enzyme Inhib Med Chem ; 34(1): 1233-1246, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31286784

RESUMO

Neratinib is an oral pan HER inhibitor, that irreversibly inhibits EGFR and HER2 and was proven to be effective against multiple EGFR mutations. In previous study, we reported spiro [indoline-3, 4'-piperidine]-2-ones as anticancer agents. In this study, we designed aminopyridine-containing spiro [indoline-3,4'-piperidine] derivatives A1-A4 using Neratinib and spiro [indoline-3, 4'-piperidine]-2-one compound patented as lead structure, then replaced piperidine with cyclopropane to obtain B1-B7 and replaced indoline with benzmorpholine to get C1-C4 and D1-D2. We synthesized these compounds and evaluated their residual activities under 0.5 M drug concentration on EGFR and ERBB2. Most of compounds showed stronger inhibition on EGFR-wt and ERBB2, in which A1-A4 showed excellent inhibitory activity with inhibition percentage on EGFR-wt kinase of 7%, 6%, 19%, 27%, respectively and 9%, 5%, 12%, 34% on ERBB2 kinase compared with 2% and 6% of Neratinib.


Assuntos
Aminopiridinas/química , Descoberta de Drogas , Fator de Crescimento Epidérmico/antagonistas & inibidores , Mutação , Compostos de Espiro/farmacologia , Fator de Crescimento Epidérmico/genética , Simulação de Acoplamento Molecular , Espectroscopia de Prótons por Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Compostos de Espiro/química
17.
J Enzyme Inhib Med Chem ; 34(1): 1259-1270, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31287341

RESUMO

Pyrazolylphthalimide derivative 4 was synthesized and reacted with different reagents to afford the target compounds imidazopyrazoles 5-7, pyrazolopyrimidines 9, 12, 14 and pyrazolotriazines 16, 17 containing phthalimide moiety. The prepared compounds were established by different spectral data and elemental analyses. Additionally, all synthesized derivatives were screened for their antibacterial activity against four types of Gram + ve and Gram-ve strains, and for antifungal activity against two fungi micro-organisms by well diffusion method. Moreover, the antiproliferative activity was tested for all compounds against human liver (HepG-2) cell line in comparison with the reference vinblastine. Moreover, drug-likeness and toxicity risk parameters of the newly synthesized compounds were calculated using in silico studies. The data from structure-actvity relationship (SAR) analysis suggested that phthalimide derivative bearing 3-aminopyrazolone moiety, 4 illustrated the best antimicrobial and antitumor activities and might be considered as a lead for further optimization. To investigate the mechanism of the antimicrobial and anticancer activities, enzymatic assay and molecular docking studies were carried out on E. coli topoisomerase II DNA gyrase B and VEGFR-2 enzymes.


Assuntos
Ftalimidas/química , Ftalimidas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Ftalimidas/síntese química , Análise Espectral/métodos , Relação Estrutura-Atividade
18.
J Enzyme Inhib Med Chem ; 34(1): 1287-1297, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31288582

RESUMO

Inhibition of NF-κB signalling has been demonstrated as a therapeutic option in treating inflammatory diseases and cancers. Herein, we synthesized novel dissymmetric 3,5-bis(arylidene)-4-piperidones (BAPs, 83-102) and characterized fully. MTT and ELISA assay were performed to screen the anti-hepatoma and anti-inflammation properties. 96 showed the most potential bioactivity. 96 could promote HepG2 apoptosis through up-regulating the expression of C-Caspase-3 and Bax, down-regulating the expression of Bcl-2, while markedly inhibit LPS or TNF-α-induced activation of NF-κB through both inhibiting the phosphorylation of IκBα and p65, and preventing the p65 nuclear translocation to exhibit both anti-hepatoma and anti-inflammatory activities. Molecular docking verified that simulated 96 can effectively bond to the active site of Bcl-2 and NF-κB/p65 proteins. 96 inhibited xenografts growth by reducing the expression of TNF-α and Bcl-2 in the tumour tissue. This study suggested that 96 could be developed as a potential multifunctional agent for treatment of inflammatory diseases and cancers.


Assuntos
Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Carcinoma Hepatocelular/prevenção & controle , Inflamação/prevenção & controle , Neoplasias Hepáticas/prevenção & controle , NF-kappa B/metabolismo , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Neoplasias Hepáticas/patologia , Simulação de Acoplamento Molecular
19.
Plant Foods Hum Nutr ; 74(3): 405-413, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31273642

RESUMO

The aim of this work was to evaluate the ability of broken rice, an underutilized industrial by-product, as a potential functional and health promoting ingredient. With this purpose, the ability to inhibit the angiotensin converting enzyme and renin of a rice protein hydrolyzate (RPH) obtained from a high-protein variety of broken rice (var. Nutriar FCAyF) was analyzed (IC50 = 0.87 and 2.7 mg/mL, respectively). RPH was separated by gel permeation chromatography and in a second purification step by RP-HPLC. The sequence of antihypertensive peptides presented in two RP-HPLC fractions was analyzed. Peptides capable of interacting with the active sites of both enzymes were identified. In this study, we demonstrate that the hydrolysis treatment improves functional and biological properties of rice proteins. Protein preparations obtained from a by-product of rice industry, such as broken rice, are a promising ingredient with potentially good biological properties.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Hipertensivos/isolamento & purificação , Oryza/química , Peptídeos/isolamento & purificação , Renina/antagonistas & inibidores , Anti-Hipertensivos/farmacologia , Cromatografia Líquida de Alta Pressão , Promoção da Saúde , Hidrólise , Simulação de Acoplamento Molecular , Peptídeos/farmacologia , Peptidil Dipeptidase A/metabolismo , Proteínas de Plantas/antagonistas & inibidores , Proteínas de Plantas/metabolismo , Renina/metabolismo
20.
J Agric Food Chem ; 67(32): 8896-8904, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31339308

RESUMO

The mosquito Aedes aegypti is associated with the spread of many viral diseases in humans, including Dengue virus (DENVs), Yellow fever virus (YFV), Zika virus (ZIKV), and Chikungunya virus (CHIKV). Bacillus thuringiensis (Bt) is widely used as a biopesticide, which produces Cry toxins for mosquito control. The Cry toxins bind mainly to important receptors, including alkaline phosphatase (ALP) and aminopeptidase-N (APN). This work investigated the function of a C-type lectin, CTLGA9, in A. aegypti in response to Cry toxins. Our results showed by far-western blot and ELISA methods that the CTLTGA9 protein interacted with brush border membrane vesicles (BBMVs) of A. aegypti larvae and with ALP1, APN, and Cry11Aa proteins. Furthermore, molecular docking showed overlapping binding sites in ALP1 and APN for binding to Cry11Aa and CTLGA9. The toxicity assays further demonstrated that CTLGA9 inhibited the larvicidal activity of Cry toxins. According to the results of molecular docking, CTLGA9 may compete with Cry11Aa for binding to ALP1 and APN receptors and thus decreases the mosquitocidal toxicity of Cry11Aa. Our results provide further insights into better understanding the mechanism of Cry toxins and help improve the Cry toxicity for mosquito control.


Assuntos
Aedes/efeitos dos fármacos , Aedes/metabolismo , Proteínas de Bactérias/toxicidade , Endotoxinas/toxicidade , Proteínas Hemolisinas/toxicidade , Proteínas de Insetos/metabolismo , Aedes/química , Aedes/genética , Animais , Proteínas de Bactérias/química , Sítios de Ligação , Endotoxinas/química , Proteínas Hemolisinas/química , Proteínas de Insetos/química , Proteínas de Insetos/genética , Larva/efeitos dos fármacos , Larva/genética , Larva/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica/efeitos dos fármacos
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