Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 11 de 11
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
3.
Comput Biol Chem ; 92: 107481, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33838390

RESUMO

In this study, firstly, the pharmacophore model was established based on LAR inhibitors. ZINC database and drug-like database were screened by Hypo-1-LAR model, and the embryonic compound ZINC71414996 was obtained. Based on this compound, we designed 9 compounds. Secondly, the synthetic route of the compound was determined by consulting Reaxys and Scifinder databases, and 9 compounds (1a-1i) were synthesized by nucleophilic substitution, Suzuki reaction and so on. Meanwhile, their structures were confirmed by 1H NMR and 13C NMR. Thirdly, the Enzymatic assays was carried out, the biological evaluation of compounds 1a-1i led to the identification of a novel PTP-LAR inhibitor 1c, which displayed an IC50 value of 4.8 µM. At last, molecular dynamics simulation showed that compounds could interact strongly with the key amino acids LYS1350, LYS1352, ARG1354, TYR1355, LYS1433, ASP1435, TRP1488, ASP1490, VAL1493, SER1523, ARG1528, ARG1561, GLN1570, LYS1681, thereby inhibiting the protein activity. This study constructed the pharmacophore model of LAR protein, designed small-molecule inhibitors, conducted compound synthesis and enzyme activity screening, so as to provide a basis for searching for drug-capable lead compounds.


Assuntos
Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estrutura Molecular , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
4.
Mol Divers ; 25(3): 1873-1887, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33392964

RESUMO

The E69K mutation is one of the most frequent protein tyrosine phosphatase-2 (SHP2) mutations in leukemia, and it can cause the increase in the protein activity. Recent studies have shown that the E69K mutation was fairly sensitive to the allosteric inhibitor of SHP2 (SHP099). However, the molecular mechanism of the allosteric drug SHP099 inhibiting SHP2E69K remains unclear. Thus, the molecular dynamic simulations and the post-dynamics analyses (RMSF, PCA, DCCM, RIN and the binding free energies) for SHP2WT, SHP2WT-SHP099, SHP2E69K and SHP2E69K-SHP099 were carried out, respectively. Owing to the strong binding affinity of SHP099 to residues Thr219 and Arg220, the flexibility of linker region (residues Val209-Arg231) was reduced. Moreover, the presence of SHP099 kept the autoinhibition state of the SHP2 protein through enhancing the interactions between the linker region and Q loop in PTP domain, such as Thr219/Val490, Thr219/Asn491, Arg220/Ile488 and Leu254/Asn491. In addition, it was found that the residues (Thr219, Arg220, Leu254 and Asn491) might be the key residues responsible for the conformational changes of protein. Overall, this study may provide an important basis for understanding how the SHP099 effectively inhibited the SHP2E69K activity at the molecular level.

5.
J Mol Graph Model ; 103: 107807, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33338846

RESUMO

Abnormal activation of Ras/MAPK signaling pathway could trigger excessive cell division. Src-homology 2 (SH2) domain-containing protein tyrosine phosphatase (SHP2) could promote Ras/MAPK activation by integrating growth factor signals. Thus, SHP2 inhibitors had become a hot topic in the treatment of cancer. SHP2F285S, mutation in SHP2, was detected in leukemia variants. The compound 2 (3-benzyl-8-chloro-2-hydroxy-4H-benzo[4,5]thiazolo[3,2-a]pyrimidin-4-one) had been reported that it was a potent allosteric inhibitor of both SHP2 wild type (SHP2WT) and the F285S mutant (SHP2F285S). However, the mechanism of inhibition remained to be further discovered. Herein, molecular docking and molecular dynamic (MD) simulation were performed to explain the inhibition mechanism of compound 2 on SHP2WT and SHP2F285S. Overall, the molecular docking analysis revealed that compound 2 maintained the "close" structure of SHP2 protein probably by locking the C-SH2 and PTP domain. Next, post-analysis demonstrated that compound 2 might make TYR66-GLU76 of D'E-loop in N-SH2 and GLU258-LYS266 of B'C-loop, HIS458-ARG465 of P-loop, VAL497-THR507 of Q-loop in PTP domain regions tightly connect and much easier maintain "self-inhibited" conformation of SHP2F285S-compound2 than that of SHP2WT-compound2. Importantly, GLU76 of D'E-loop could play a vital role in inhibition of SHP2WT-compound2 and SHP2F285S-compound2. This work provided a reliable clue to develop novel inhibitors for leukemia related to SHP2F285S.


Assuntos
Simulação de Dinâmica Molecular , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Conformação Molecular , Simulação de Acoplamento Molecular , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo
6.
J Biomol Struct Dyn ; 38(18): 5338-5348, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31787068

RESUMO

The overexpression of PTP-LAR could cause the insulin resistance, so PTP-LAR might be a promising target for treating diabetes. In this study, we applied the computer modeling methods with fragment replace approach to screen the fragment database by targeting PTP domain and site B with the aim to discover potent and selective PTP-LAR inhibitors. A series of novel 4-thiazolidone derivatives were gained. The results of their ADMET predictions indicated that these new compounds might become drug candidates. The series of these derivatives were synthesized. Subsequently, their PTP-LAR inhibitory activities were assayed. The compound7d showed highly selectivity for PTP-LAR (10.41 µM) over its close homolog PTP1B (IC50=44.40 µM), SHP2 (IC50>122.81 µM) and CDC25B (IC50>122.81 µM) and docking and molecular dynamics simulation were applied to propose the most likely binding mode of compound7d with PTP-LAR. Thus, our findings reported here may pave a way for discovering potential selective PTP-LAR inhibitors.AbbreviationsPTP-LARHuman leukocyte common antigen-relatedPTPProtein Tyrosine PhosphataseIRinsulin receptorPTP1BProtein tyrosine phosphatase-1BLRPLung resistance proteinADMETabsorption, distribution, metabolism, excretion, toxicityPPBplasma protein bindingBBBblood brain barrier penetrationCYP450cytochrome P450HIAhuman intestinal absorptionTLCthin-layer chromatographyUVUltra VioletNMRnuclear magnetic resonanceTMStetramethylsilaneMSmass spectrometryANManisotropic network modePDBProtein Data BankDMFN,N-DimethylformamidepNPPpara-nitrophenyl phosphateDTTdithiothreitolMDmolecular dynamicRMSDroot-mean-square deviationRMSFroot-mean-square fluctuationSPCsingle-point chargePMEParticle Mesh EwaldMM-PBSAmolecular mechanics Poisson Boltzmann surface areaH bond, hydrogen bondVDWVan der WaalsCommunicated by Ramaswamy H. Sarma.


Assuntos
Diabetes Mellitus , Inibidores Enzimáticos , Antígenos Comuns de Leucócito , Simulação por Computador , Diabetes Mellitus/tratamento farmacológico , Antígenos HLA , Humanos
7.
Comput Biol Chem ; 83: 107123, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31561070

RESUMO

The low molecular weight protein tyrosine phosphatase (LMW-PTP) could regulate many signaling pathways, and it had drawn attention as a potential target for cancer. As previous report has indicated that the aplidin could inhibit the LMW-PTP, and thus, the relevant cancer caused by the abnormal regulation of the LMW-PTP could be remission. However, the molecular mechanism of inhibition of the LMW-PTP by the aplidin had not been fully understood. In this study, various computational approaches, namely molecular docking, MDs and post-dynamic analyses were utilized to explore the effect of the aplidin on the LMW-PTP. The results suggested that the intramolecular interactions of the residues in the two sides of the active site (Ser43-Ala55 and Pro121-Asn134) and the P-loop region (Leu13-Ser19) in the LMW-PTP was disturbed owing to the aplidin, meanwhile, the π-π interaction between Tyr131 and Tyr132 might be broken. The Asn15 might be the key residue to break the residues interactions. In a word, this study may provide more information for understanding the effect of inhibition of the aplidin on the LMW-PTP.


Assuntos
Depsipeptídeos/farmacologia , Inibidores Enzimáticos/farmacologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Domínio Catalítico/efeitos dos fármacos , Depsipeptídeos/química , Inibidores Enzimáticos/química , Humanos , Conformação Molecular , Peso Molecular , Proteínas Tirosina Fosfatases/química , Proteínas Tirosina Fosfatases/metabolismo
8.
Bioorg Med Chem Lett ; 29(3): 383-388, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30579795

RESUMO

As a part of our ongoing research to develop novel URAT1 inhibitors, 19 compounds (1a-1s) based on carboxylic acid bioisosteres were synthesized and tested for in vitro URAT1 inhibitor activity (IC50). The structure-activity relationship (SAR) exploration led to the discovery of a highly potent novel URAT1 inhibitor 1g, which was 225-fold more potent than the parent lesinurad in vitro (IC50 = 0.032 µM for 1g against human URAT1 vs 7.20 µM for lesinurad). Besides, 3D-QSAR pharmacophore models were established based on the activity of the compounds (1a-1s) by Accelrys Discovery Studio 2.5/HypoGen. The best hypothesis, Hypo 1, was validated by three methods (cost analysis, Fisher's randomization and leave-one-out). Although compound 1g is among the most potent URAT1 inhibitors currently under development in clinical trials, the Hypo1 appears to be favorable for future lead optimization.


Assuntos
Ácidos Carboxílicos/farmacologia , Ésteres/farmacologia , Gota/tratamento farmacológico , Hiperuricemia/tratamento farmacológico , Transportadores de Ânions Orgânicos/antagonistas & inibidores , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Relação Quantitativa Estrutura-Atividade , Triazóis/farmacologia , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/química , Relação Dose-Resposta a Droga , Ésteres/síntese química , Ésteres/química , Gota/metabolismo , Humanos , Hiperuricemia/metabolismo , Estrutura Molecular , Transportadores de Ânions Orgânicos/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Triazóis/química
9.
Rev Sci Instrum ; 88(9): 093104, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28964165

RESUMO

We demonstrate theoretically and experimentally a coherent terahertz detection technique based on an optically biased field functioning as a local oscillator and a second harmonic induced by the terahertz electric field in the air sensor working in free space. After optimizing the polarization angle and the energy of the probe pulse, and filling the system with dry nitrogen, the terahertz radiation generated from a two-color-femtosecond-laser-pulses induced plasma filament is measured by this technique with a bandwidth of 0.1-10 THz and a signal-to-noise ratio of 48 dB. Our technique provides an alternative simple method for coherent broadband terahertz detection.

10.
Comb Chem High Throughput Screen ; 17(10): 837-47, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25360618

RESUMO

The cell division cycle 25 (Cdc25) family of proteins is a group of highly conserved dual specificity phosphatases that regulate cyclin-dependent kinases and represent a group of attractive drug targets for anticancer therapies. To develop novel Cdc25B inhibitors, the ZINC database was screened for finding optimal fragments with de novo design approaches. As a result, top 11 compounds with higher binding affinities in flexible docking were obtained, which were derived from five novel scaffolds (scaffold C) consisting of the linker-part and two isolated scaffolds (scaffold A and B)located in the two binding domains (catalytic pocket and swimming pool), respectively. The subsequent molecular docking and molecular dynamics studies showed that these compounds not only adopt more favorable conformations but also have stronger binding interaction with receptor than the inhibitors identified previously. The additional absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions also indicted that the 11 compounds (especially Comp#1) hold a high potential to be novel lead compounds for anticarcinogen. Consequently, the findings reported here may at least provide a new strategy or useful insights for designing effective Cdc25B inhibitors.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Domínio Catalítico/efeitos dos fármacos , Desenho de Fármacos , Neoplasias/tratamento farmacológico , Fosfatases cdc25/antagonistas & inibidores , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Neoplasias/metabolismo , Fosfatases cdc25/química , Fosfatases cdc25/metabolismo
11.
Ground Water ; 52(5): 798-807, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24032445

RESUMO

Groundwater recharge is an important component of the groundwater system. On the North China Plain (NCP), groundwater is the main water supply. Because of large-scale overexploitation, the water table has declined, which has produced severe adverse effects on the environment and ecosystem. In this article, tracer experiment and watershed model were used to calculate and analyze NCP groundwater recharge. In the tracer experiment, average recharge was 108 mm/year and recharge coefficient 0.16. With its improved irrigation, vegetation coverage and evapotranspiration modules, the INFIL3.0 model was used for calculation of groundwater recharge. Regional modeling results showed an average recharge of 102 mm/year and recharge coefficient 0.14, for 2001-2009. These values are very similar to those from the field tracer experiment. Influences in the two methods were analyzed. The results can provide an important reference for NCP groundwater recharge.


Assuntos
Água Subterrânea/análise , Movimentos da Água , Abastecimento de Água/análise , China , Monitoramento Ambiental , Modelos Teóricos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...