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1.
Nat Commun ; 12(1): 815, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547286

RESUMO

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.


Assuntos
Aminopiridinas/química , Azepinas/química , Antagonistas dos Receptores de Orexina/química , Receptores de Orexina/química , Peptídeos/química , Medicamentos Indutores do Sono/química , Sulfonamidas/química , Triazóis/química , Aminopiridinas/metabolismo , Azepinas/metabolismo , Sítios de Ligação , Clonagem Molecular , Microscopia Crioeletrônica , Escherichia coli/genética , Escherichia coli/metabolismo , Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Células HEK293 , Humanos , Simulação de Dinâmica Molecular , Antagonistas dos Receptores de Orexina/metabolismo , Receptores de Orexina/agonistas , Receptores de Orexina/metabolismo , Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Medicamentos Indutores do Sono/metabolismo , Sulfonamidas/metabolismo , Triazóis/metabolismo
2.
Gene ; 776: 145445, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33484758

RESUMO

Glioblastom Multiforme (GBM) is the most invasive and malignant member of the IV grade of the subclass Astrocytoma according to the last assessment of the 2016 WHO report. Due to the resistance to treatment and weak response, as well as the topographical structure of the blood brain barrier, the treatment is also difficult due to the severe clinical manifestation, and new treatment methods and new therapeutic agents are needed. Temozolomide (TMZ) is widely used in the treatment of glioblastoma and is considered as the primary treatment modality. TMZ, a member of the class of cognitive agents, is currently considered the most effective drug because it can easily pass through the blood brain barrier. Glucose metabolism is a complex energy producing machine that, a glucose molecule produces 38 molecules of ATP after full glycolytic catabolism. According to Otto Warburg's numerous studies cancer cells perform the first glycolytic step without entering the mitochondrial step. These cells produce lactic acid and make the micro-media more acidic even in aerobic conditions. This phenomenon is attributed to the Warburg hypothesis and either as aerobic glycolysis. Although glycolysis enzymes are the primary actors of this phenotypic expression, some genetic and epigenetic factors are no exception. We experimentally used KC7F2 active ingredient to target cancer metabolism. In our study, we evaluated cancer metabolism in combination with the effect of TMZ chemotherapeutic agent, examining the effect of two different agents separately and in combination to observe the effects of cancer cell proliferation, survival, apoptosis and expression of metabolism genes on expression. We observed that the combined effect of reduced the effective dose of the TMZ alkylating agent and that the effect was increased and the effect of the combined teraphy is assessed from a metabolic point of view and that it suppresses aerobic glycolysis.


Assuntos
Dissulfetos/farmacologia , Glioma/tratamento farmacológico , Sulfonamidas/farmacologia , Temozolomida/farmacologia , Antineoplásicos/farmacologia , Antineoplásicos Alquilantes/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dissulfetos/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/patologia , Glioma/patologia , Glucose/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Sulfonamidas/metabolismo , Temozolomida/metabolismo
3.
Chemosphere ; 262: 128026, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33182090

RESUMO

The objective of the study was to assess the applicability of the mycelium obtained from the in vitro cultures of nontoxic bracket fungus, Pleurotus eryngii, to sulfonamides mycodegradation. Samples containing one of the six selected sulfonamides, sulfanilamide derivatives, were incubated with the mycelium of P. eryngii for 7 and 14 days in vitro. Subsequently, change in the sulfonamide concentration was assessed in the samples using the UPLC-QTof. The transformation products were identified based on monoisotopic molecular mass and fragmentation spectra. The studied sulfonamides did not inhibit the growth of P. eryngii mycelium in the in vitro cultures. In addition, a considerable reduction of sulfonamide concentration was observed in all the incubated samples (from 73.7 ± 8.3% to 99.8 ± 0.3%). In the case of three sulfonamides, the reduction in concentration >90% occurred after 7 days of incubation. However, the transformation of sulfonamides was partially caused by their degradation to simpler organic compounds. After incubation, the products of condensation of sulfonamides with formyl, acyl, and sugar groups, and amino acid-derived compounds were identified in the samples. This indicated the partially reversible nature of the mycodegradation process.


Assuntos
Poluentes Ambientais/análise , Modelos Teóricos , Micélio/metabolismo , Pleurotus/metabolismo , Sulfonamidas/análise , Biodegradação Ambiental , Biomassa , Carboidratos/análise , Poluentes Ambientais/metabolismo , Micélio/crescimento & desenvolvimento , Pleurotus/crescimento & desenvolvimento , Sulfonamidas/metabolismo
4.
Chemosphere ; 261: 127604, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32750616

RESUMO

Residual veterinary antibiotics have been detected in livestock wastewater treatment plants. Despite the long retention time, antibiotic treatment efficiency has shown clear limitations. In this study, we evaluated submerged membrane photobioreactors (SMPBR) during sulfonamide antibiotic-containing livestock wastewater treatment under mixotrophic and photoautotrophic conditions. The results showed that microalgal sulfur degradation and consumption under mixotrophic conditions accelerated the biomass concentration increase to 2800 mg VSS/L compared to the 1800 mg VSS/L measured under photoautotrophic conditions. Although microalgal metabolites, such as soluble microbial products and extracellular polymeric substances, might cause membrane fouling in the SMPBR, we proved that microalgae could remove sulfonamide and release degradation-associated sulfur, along with nitrogen and phosphorus. Moreover, this study confirms the statistical correlation between metabolites and sulfonamides. In summary, the results of this study provide promising insights into antibiotic-containing livestock wastewater treatment.


Assuntos
Fotobiorreatores , Sulfonamidas/metabolismo , Animais , Biomassa , Gado/metabolismo , Microalgas/metabolismo , Nitrogênio/análise , Fósforo/metabolismo , Sulfanilamida , Águas Residuárias
5.
Bull Environ Contam Toxicol ; 105(4): 595-601, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32862252

RESUMO

The residual characteristics and risk assessment with respect to cyazofamid and its metabolite 4-chloro-5-p-tolylimidazole-2-carbonitrile were monitored in case of Korean cabbage at different preharvest intervals during a greenhouse trial. The 0.02 kg a.i/ha of cyazofamid was sprayed twice on seven-day intervals (i.e., on day 0, 7, 14, and 21 before harvest). The liquid chromatography-tandem mass spectrometry analysis was used to monitor the residual amount of fungicide. The matrix-matched calibration curves with respect to the cyazofamid in Korean cabbage exhibited good linearity (R2 ≥ 0.999) and acceptable recoveries of 84.1%-114.9%. The biological half-life of cyazofamid in Korean cabbage was 3.18 days. During the treatment, the preharvest residue of cyazofamid in Korean cabbage 14 days before harvest (0.80 mg/kg) was lower than that specified by the MFDS-MRL (Ministry of Food and Drug Safety-Maximum Residue Limit, 2.0 mg/kg) and should be recommended as the safe preharvest-interval application limit. The hazard quotient showed low toxicity (70.58%) during the risk assessment study of cyazofamid.


Assuntos
Fungicidas Industriais/toxicidade , Imidazóis/toxicidade , Resíduos de Praguicidas/toxicidade , Sulfonamidas/toxicidade , Brassica/química , Cromatografia Líquida/métodos , Fungicidas Industriais/química , Fungicidas Industriais/metabolismo , Meia-Vida , Imidazóis/metabolismo , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/metabolismo , República da Coreia , Medição de Risco , Sulfonamidas/metabolismo
6.
J Med Chem ; 63(11): 6066-6089, 2020 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-32421339

RESUMO

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) have been suggested to be effective anti-HBV agents in both preclinical and clinical studies. In addition to blocking HBV replication, CAMs could reduce the formation of covalently closed circular DNA (cccDNA), which accounts for the persistence of HBV infection. Here, we describe the discovery of (1H-indazole-5-yl)sulfonamides and (1H-pyrazolo[3,4-c]pyridin-5-yl)sulfonamides as new CAM chemotypes by constraining the conformation of the sulfamoylbenzamide derivatives. Lead optimization resulted in compound 56 with an EC50 value of 0.034 µM and good metabolic stability in mouse liver microsomes. To increase the solubility, the amino acid prodrug (65) and its citric acid salt (67) were prepared. Compound 67 dose dependently inhibited HBV replication in a hydrodynamic injection-based mouse model of HBV infection, while 56 did not show in vivo anti-HBV activity, likely owing to its suboptimal solubility. This class of compounds may serve as a starting point to develop novel anti-HBV drugs.


Assuntos
Antivirais/química , Capsídeo/metabolismo , Vírus da Hepatite B/fisiologia , Sulfonamidas/química , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Sítios de Ligação , Proteínas do Capsídeo/química , Proteínas do Capsídeo/metabolismo , Linhagem Celular , DNA Viral/metabolismo , Desenho de Fármacos , Farmacorresistência Viral/efeitos dos fármacos , Humanos , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Terciária de Proteína , Pirazóis/química , Piridinas/química , Solubilidade , Relação Estrutura-Atividade , Sulfonamidas/metabolismo , Sulfonamidas/farmacologia , Montagem de Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
7.
Chemosphere ; 255: 127033, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32417520

RESUMO

Symbiosis among herbicide-metabolising microorganisms and phytoremediation plants may be an efficient alternative to remediate sulfentrazone-contaminated soils. This work evaluated the bioremediation of sulfentrazone-contaminated soils by symbiosis between bacteria (Bradyrhizobium sp.) and jack bean (Canavalia ensiformis L.). The experiment was carried out in a greenhouse between March and May of 2018, in the Universidade Federal do Espírito Santo (UFES). Four doses of sulfentrazone (0, 400, 800, and 1200 g ha-1 a. i.) were tested with and without inoculation with Bradyrhizobium sp. BR 2003 (SEMIA 6156) After 80 days of cultivation, plants were cut and soil was collected for determination of the herbicide residual levels and millet bioassay. The sulfentrazone concentration was significantly reduced by plant inoculation with Bradyrhizobium sp.: on average, concentrations were 18.97%, 23.82%, and 22.10% lower than in the absence of inoculation at doses of 400, 800, and 1200 g ha-1, respectively. Symbiosis promoted a reduction of up to 65% in residual soil herbicides. Under the 1200 g ha-1 dose, inoculation promoted greater plant height than in the uninoculated plant. Regardless of the dose of sulfentrazone, the dry root mass was higher in the inoculated plants. The microbiological indicators showed satisfactory results mainly for the dose of 400 g ha-1. The results of this study highlight the potential of positive interactions between symbiotic microorganisms and leguminous species, aiming toward the phytoremediation of sulfentrazone herbicide.


Assuntos
Bradyrhizobium/crescimento & desenvolvimento , Canavalia/crescimento & desenvolvimento , Herbicidas/análise , Microbiologia do Solo , Poluentes do Solo/análise , Sulfonamidas/análise , Triazóis/análise , Biodegradação Ambiental , Herbicidas/metabolismo , Solo/química , Poluentes do Solo/metabolismo , Sulfonamidas/metabolismo , Simbiose , Triazóis/metabolismo
9.
Biosci Rep ; 40(6)2020 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-32441299

RESUMO

Due to the lack of efficient therapeutic options and clinical trial limitations, the FDA-approved drugs can be a good choice to handle Coronavirus disease (COVID-19). Many reports have enough evidence for the use of FDA-approved drugs which have inhibitory potential against target proteins of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Here, we utilized a structure-based drug design approach to find possible drug candidates from the existing pool of FDA-approved drugs and checked their effectiveness against the SARS-CoV-2. We performed virtual screening of the FDA-approved drugs against the main protease (Mpro) of SARS-CoV-2, an essential enzyme, and a potential drug target. Using well-defined computational methods, we identified Glecaprevir and Maraviroc (MVC) as the best inhibitors of SARS-CoV-2 Mpro. Both drugs bind to the substrate-binding pocket of SARS-CoV-2 Mpro and form a significant number of non-covalent interactions. Glecaprevir and MVC bind to the conserved residues of substrate-binding pocket of SARS-CoV-2 Mpro. This work provides sufficient evidence for the use of Glecaprevir and MVC for the therapeutic management of COVID-19 after experimental validation and clinical manifestations.


Assuntos
Betacoronavirus/enzimologia , Maraviroc/farmacologia , Inibidores de Proteases/farmacologia , Quinoxalinas/farmacologia , Sulfonamidas/farmacologia , Antivirais/química , Antivirais/metabolismo , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Simulação por Computador , Avaliação Pré-Clínica de Medicamentos/métodos , Maraviroc/química , Maraviroc/metabolismo , Estrutura Molecular , Inibidores de Proteases/química , Inibidores de Proteases/metabolismo , Quinoxalinas/química , Quinoxalinas/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
10.
Chemosphere ; 251: 126633, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32443228

RESUMO

Contamination by per- and polyfluoroalkyl substances (PFASs) is of great concern in global environments. Due to strong regulation of legacy PFASs, emerging PFASs including alternatives and precursors have been introduced to the industrial market. In this study, legacy and emerging PFASs were measured in seawater, sediment, and bivalves collected along the Korean coast to investigate the occurrence, distribution, contamination sources, and bioaccumulation potential of PFASs. Wide concentration ranges of legacy PFASs were detected in multiple environmental samples, indicating widespread contamination. C8-based PFASs (e.g., PFOA and PFOS) were still major contaminants in all of the environmental samples. Some precursors, such as 8:2 fluorotelomer sulfonate (8:2 FTS) and N-ethyl-perfluorooctane sulfonamidoacetic acid (N-EtFOSAA), and perfluoro-2-propoxypropanoic potassium 9-chlorohexadecafluoro-3-oxanonane-1-sulfonate (F-53B), an alternative to PFOS, were detected in sediment or bivalve samples, implying a shift in consumption patterns from legacy to emerging PFASs. The highest concentrations of PFASs in environmental samples were found at the locations near industrial complexes, such as those for the semi-conductor, paper mill, automobile, and metal-plating industry. This result indicates that PFAS contamination is associated with intensive industrial activities in the coastal environment. Matrix-dependent contamination and profiles of PFASs were observed. Seawater was dominated by short-chained PFASs as a prompt reflection of regulation, while the sediment and bivalves were dominated by long-chained PFASs. Carbon-chain length was a major factor governing environmental behavior and bioaccumulation of PFASs. This was the first nation-wide survey on legacy and emerging PFASs in the coastal environment of Korea.


Assuntos
Alcanossulfonatos/análise , Bioacumulação , Bivalves/efeitos dos fármacos , Monitoramento Ambiental/métodos , Fluorcarbonetos/análise , Sulfonamidas/análise , Poluentes Químicos da Água/análise , Alcanossulfonatos/metabolismo , Animais , Bivalves/metabolismo , Fluorcarbonetos/metabolismo , República da Coreia , Água do Mar/química , Sulfonamidas/metabolismo , Poluentes Químicos da Água/metabolismo
11.
J Med Chem ; 63(9): 4749-4761, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32240584

RESUMO

Tuberculosis (TB) remains a leading cause of mortality among infectious diseases worldwide. InhA has been the focus of numerous drug discovery efforts as this is the target of the first line pro-drug isoniazid. However, with resistance to this drug becoming more common, the aim has been to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, the screening and validation of a fragment library are described, and the development of the fragment hits using a fragment growing strategy was employed, which led to the development of InhA inhibitors with affinities of up to 250 nM.


Assuntos
Antituberculosos/química , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/química , Mycobacterium tuberculosis/enzimologia , Oxirredutases/antagonistas & inibidores , Sulfonamidas/química , Antituberculosos/síntese química , Antituberculosos/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Sítios de Ligação , Desenho de Fármacos , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Oxirredutases/química , Oxirredutases/metabolismo , Ligação Proteica , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
12.
J Med Chem ; 63(9): 4762-4775, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32297742

RESUMO

The exchange protein activated by cAMP (EPAC) is a promising drug target for a wide disease range, from neurodegeneration and infections to cancer and cardiovascular conditions. A novel partial agonist of the EPAC isoform 1 (EPAC1), I942, was recently discovered, but its mechanism of action remains poorly understood. Here, we utilize NMR spectroscopy to map the I942-EPAC1 interactions at atomic resolution and propose a mechanism for I942 partial agonism. We found that I942 interacts with the phosphate binding cassette (PBC) and base binding region (BBR) of EPAC1, similar to cyclic adenosine monophosphate (cAMP). These results not only reveal the molecular basis for the I942 vs cAMP mimicry and competition, but also suggest that the partial agonism of I942 arises from its ability to stabilize an inhibition-incompetent activation intermediate distinct from both active and inactive EPAC1 states. The mechanism of action of I942 may facilitate drug design for EPAC-related diseases.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/metabolismo , Sulfonamidas/metabolismo , Sítio Alostérico , Arginina/química , AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/agonistas , Fatores de Troca do Nucleotídeo Guanina/química , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Eletricidade Estática , Sulfonamidas/química
13.
J Med Chem ; 63(10): 5212-5241, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32321240

RESUMO

Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/antagonistas & inibidores , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Sulfonamidas/metabolismo , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Células HEK293 , Humanos , Ligação Proteica/fisiologia , Domínios Proteicos/efeitos dos fármacos , Domínios Proteicos/fisiologia , Estrutura Secundária de Proteína , Sulfonamidas/química , Sulfonamidas/farmacologia
14.
J Med Chem ; 63(9): 4880-4895, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32298120

RESUMO

Due to their role in many important signaling pathways, phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are attractive targets for the development of experimental therapeutics for cancer, metabolic, and immunological disorders. Recent efforts to develop small molecule inhibitors for these lipid kinases resulted in compounds with low- to sub-micromolar potencies. Here, we report the identification of CVM-05-002 using a high-throughput screen of PI5P4Kα against our in-house kinase inhibitor library. CVM-05-002 is a potent and selective inhibitor of PI5P4Ks, and a 1.7 Å X-ray structure reveals its binding interactions in the ATP-binding pocket. Further investigation of the structure-activity relationship led to the development of compound 13, replacing the rhodanine-like moiety present in CVM-05-002 with an indole, a potent pan-PI5P4K inhibitor with excellent kinome-wide selectivity. Finally, we employed isothermal cellular thermal shift assays (CETSAs) to demonstrate the effective cellular target engagement of PI5P4Kα and -ß by the inhibitors in HEK 293T cells.


Assuntos
Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Sulfonamidas/farmacologia , Tiazolidinas/farmacologia , Cristalografia por Raios X , Descoberta de Drogas , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Estrutura Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Ligação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/metabolismo , Piridinas/síntese química , Piridinas/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo , Tiazolidinas/síntese química , Tiazolidinas/metabolismo
15.
J Med Chem ; 63(9): 4655-4684, 2020 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-32118427

RESUMO

A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (1), a unique aryl acylsulfonohydrazide with an IC50 of 1.0 µM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as 55 and 80. These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 (3) as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (4). This compound is a highly potent KAT6A inhibitor (IC50 = 6.3 nM; KD = 0.002 µM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.


Assuntos
Antineoplásicos/farmacologia , Histona Acetiltransferases/antagonistas & inibidores , Hidrazinas/farmacologia , Sulfonamidas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/metabolismo , Descoberta de Drogas , Estabilidade de Medicamentos , Humanos , Hidrazinas/síntese química , Hidrazinas/metabolismo , Masculino , Camundongos , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
16.
Metabolism ; 111S: 154203, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32151660

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease and important unmet medical need. Current guidelines recommend, under specific restrictions, pioglitazone or vitamin E in patients with NASH and significant fibrosis, but the use of both remains off-label. We summarize evidence on medications for the treatment of nonalcoholic steatohepatitis (NASH), since NASH has been mainly associated with higher morbidity and mortality. Some of these medications are currently in phase 3 clinical trials, including obeticholic acid (a farnesoid X receptor agonist), elafibranor (a peroxisome proliferator activated receptor [PPAR]-α/δ dual agonist), cenicriviroc (a CC chemokine receptor antagonist), MSDC-0602 K (a PPAR sparing modulator), selonsertib (an apoptosis signal-regulating kinase-1 inhibitor) and resmetirom (a thyroid hormone receptor agonist). A significant research effort is also targeting PPARs and selective PPAR modulators, including INT131 and pemafibrate, with the expectation that novel drugs may have beneficial effects similar to those of pioglitazone, but without the associated adverse effects. Whether these and other medications could offer tangible therapeutic benefits, alone or in combination, apparently on a background of lifestyle modification, i.e. exercise and a healthy dietary pattern (e.g. Mediterranean diet) remain to be proven. In conclusion, major advances are expected for the treatment of NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Animais , Ensaios Clínicos Fase III como Assunto , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/metabolismo , Quinolinas/metabolismo , Sulfonamidas/metabolismo
17.
PLoS One ; 15(3): e0228461, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32160194

RESUMO

Simulating drug binding and unbinding is a challenge, as the rugged energy landscapes that separate bound and unbound states require extensive sampling that consumes significant computational resources. Here, we describe the use of interactive molecular dynamics in virtual reality (iMD-VR) as an accurate low-cost strategy for flexible protein-ligand docking. We outline an experimental protocol which enables expert iMD-VR users to guide ligands into and out of the binding pockets of trypsin, neuraminidase, and HIV-1 protease, and recreate their respective crystallographic protein-ligand binding poses within 5-10 minutes. Following a brief training phase, our studies shown that iMD-VR novices were able to generate unbinding and rebinding pathways on similar timescales as iMD-VR experts, with the majority able to recover binding poses within 2.15 Å RMSD of the crystallographic binding pose. These results indicate that iMD-VR affords sufficient control for users to carry out the detailed atomic manipulations required to dock flexible ligands into dynamic enzyme active sites and recover crystallographic poses, offering an interesting new approach for simulating drug docking and generating binding hypotheses.


Assuntos
Protease de HIV/metabolismo , Simulação de Dinâmica Molecular , Neuraminidase/metabolismo , Tripsina/metabolismo , Realidade Virtual , Benzamidinas/metabolismo , Sítios de Ligação , Carbamatos/metabolismo , Furanos , Ligantes , Oseltamivir/metabolismo , Ligação Proteica , Sulfonamidas/metabolismo , Zanamivir/metabolismo
18.
J Med Chem ; 63(6): 3317-3326, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32031797

RESUMO

The design of three dual-tailed sulfonamide series 11a-11g, 14a-14h, and 16a-16e as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors are presented. All compounds were evaluated for inhibitory action against pharmacologically relevant human CA isoforms I, II, IV, and VII. Compounds 11a-11g emerged as potent CA inhibitors against the four tested isoforms with a significant selectivity to CA II, which is implicated in glaucoma (Ki in the range 0.36-6.9 nM). X-ray crystallographic analysis of three compounds (11a, 11d, and 11g) bound to CA II showed the validity of the adopted drug design strategy as specific moieties within the ligand structure interacted directly with the hydrophobic and hydrophilic halves of the CA II active site. Compounds 11b-11d and 11g were evaluated for their intraocular pressure-lowering effects in a rabbit model of glaucoma. 11b and 11d showed significant efficacy when compared to the clinically used drug dorzolamide.


Assuntos
Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Glaucoma/tratamento farmacológico , Pressão Intraocular/efeitos dos fármacos , Sulfonamidas/uso terapêutico , Animais , Inibidores da Anidrase Carbônica/síntese química , Inibidores da Anidrase Carbônica/metabolismo , Anidrases Carbônicas/química , Domínio Catalítico , Cristalografia por Raios X , Desenho de Fármacos , Humanos , Masculino , Estrutura Molecular , Ligação Proteica , Coelhos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/metabolismo
19.
Phys Chem Chem Phys ; 22(8): 4464-4480, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32057044

RESUMO

Infection by human immunodeficiency virus type 1 (HIV-1) not only destroys the immune system bringing about acquired immune deficiency syndrome (AIDS), but also induces serious neurological diseases including behavioral abnormalities, motor dysfunction, toxoplasmosis, and HIV-1 associated dementia. The emergence of HIV-1 multidrug-resistant mutants has become a major problem in the therapy of patients with HIV-1 infection. Focusing on the wild type (WT) and G48T/L89M mutated forms of HIV-1 protease (HIV-1 PR) in complex with amprenavir (APV), indinavir (IDV), ritonavir (RTV), and nelfinavir (NFV), we have investigated the conformational dynamics and the resistance mechanism due to the G48T/L89M mutations by conducting a series of molecular dynamics (MD) simulations and free energy (MM-PBSA and solvated interaction energy (SIE)) analyses. The simulation results indicate that alterations in the side-chains of G48T/L89M mutated residues cause the inner active site to increase in volume and induce more curling of the flap tips, which provide the main contributions to weaker binding of inhibitors to the HIV-1 PR. The results of energy analysis reveal that the decrease in van der Waals interactions of inhibitors with the mutated PR relative to the wild-type (WT) PR mostly drives the drug resistance of mutations toward these four inhibitors. The energy decomposition analysis further indicates that the drug resistance of mutations can be mainly attributed to the change in van der Waals and electrostatic energy of some key residues (around Ala28/Ala28' and Ile50/Ile50'). Our work can give significant guidance to design a new generation of anti-AIDS inhibitors targeting PR in the therapy of patients with HIV-1 infection.


Assuntos
Protease de HIV/metabolismo , Simulação de Dinâmica Molecular , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Furanos , Protease de HIV/genética , Indinavir/química , Indinavir/metabolismo , Conformação Molecular , Mutação , Nelfinavir/química , Nelfinavir/metabolismo , Ligação Proteica , Ritonavir/química , Ritonavir/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
20.
Behav Neurol ; 2020: 2476861, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32089749

RESUMO

Background: The aim of this study was to explore the role of hesperadin in intracerebral hemorrhage (ICH) mice, with the involvement of the mammalian ste20-like kinase 4 (MST4)/AKT signaling pathway. Methods: All mice were divided into four groups: sham group, sham+hesperidin group, ICH group, and ICH+hesperadin group. The effects of hesperadin were assessed on the basis of brain edema and neurobehavioral function. Furthermore, we observed MST4, AKT, phosphorylation of AKT (pAKT), and microtubule-associated protein light chain 3 (LC3) by western blotting. Protein localization of MST4 and LC3 was determined by immunofluorescence. Results: The expression of MST4 was upregulated at 12 h and 24 h after ICH. Brain edema was significantly decreased and neurological function was improved in the hesperadin treatment group compared to the ICH group (P < 0.05). Hesperadin decreases the expressions of MST and increases pAKT after ICH. Autophagy significantly increased in the ICH group, while hesperadin reduced this increase. Conclusion: Hesperadin provides neuroprotection against ICH by inhibiting the MST4/AKT signaling pathway.


Assuntos
Hemorragia Cerebral/fisiopatologia , Indóis/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Sulfonamidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Edema Encefálico/fisiopatologia , Hemorragia Cerebral/metabolismo , Indóis/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fármacos Neuroprotetores/farmacologia , Fosforilação , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/metabolismo
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