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1.
Int J Biol Macromol ; 146: 202-211, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31887379

RESUMO

Bacillus amyloliquefaciens is a probiotic for animals. A strain of B. amyloliquefaciens designated amy-1 was isolated from soil, and the exopolysaccharides (EPSs) of the strain were characterized in terms of their effect on glycemic control. The EPSs were composed of mannose, glucose, and galactose, with the major components being polymers larger than 1000 kDa as revealed by size-exclusion high-performance liquid chromatography. The EPSs reduced the elevation of blood glucose in mice on oral glucose tolerance tests. The hypoglycemic effect was still apparent when glucose was administered through intraperitoneal injection. Further investigation revealed that the EPSs stimulated glucagon-like peptide 1 (GLP-1) secretion from enteroendocrine cells in vitro and increased plasma GLP-1 level in vivo. Moreover, the EPSs promoted the glucose consumption of a liver cell line and an intestinal epithelial cell line. Therefore, the interaction between EPSs and intestinal tissues at least partially contributed to their hypoglycemic effect. The enhanced glucose uptake of cells was likely mediated by the activation of phosphatidylinositol-3-kinase and Akt and was independent of insulin receptor substrate and AMP-activated protein kinase. These findings suggest that EPSs likely involve in the hypoglycemic functions of probiotics and are potential new agents for glycemic control.

2.
J Org Chem ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31886669

RESUMO

We report the use of a rhodium(II) dimer in visible light photoredox catalysis for the aerobic oxidation of arylboronic acids to phenols under mild conditions. Spectroscopic and computational studies indicate that the catalyst Rh2(bpy)2(OAc)4 (1) undergoes metal-metal to ligand charge transfer upon visible light irradiation, which is responsible for catalytic activity. Further reactivity studies demonstrate that 1 is a general photoredox catalyst for diverse oxidation reactions.

3.
Chin Med J (Engl) ; 132(23): 2872-2880, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31856060

RESUMO

OBJECTIVE: Renal fibrosis is the most common manifestation of chronic kidney disease (CKD). Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it, there is an urgent need to identify novel therapies. Hydrogen sulfide (H2S) is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body. This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application. DATA SOURCES: Literature was collected from PubMed until February 2019, using the search terms including "Hydrogen sulfide," "Chronic kidney disease," "Renal interstitial fibrosis," "Kidney disease," "Inflammation factor," "Oxidative stress," "Epithelial-to-mesenchymal transition," "H2S donor," "Hypertensive kidney dysfunction," "Myofibroblasts," "Vascular remodeling," "transforming growth factor (TGF)-beta/Smads signaling," and "Sulfate potassium channels." STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files. RESULTS: The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress, inhibiting the activation of fibrosis-related cells and their cytokine expression, ameliorating vascular remodeling and high blood pressure, stimulating tubular cell regeneration, as well as reducing apoptosis, autophagy, and hypertrophy. Therefore, H2S represents an alternative or additional therapeutic approach for renal fibrosis. CONCLUSIONS: We postulate that H2S may delay the occurrence and progress of renal fibrosis, thus protecting renal function. Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.

4.
Chin Med J (Engl) ; 2019 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-31764172

RESUMO

OBJECTIVE: Renal fibrosis is the most common manifestation of chronic kidney disease (CKD). Noting that existing treatments of renal fibrosis only slow disease progression but do not cure it, there is an urgent need to identify novel therapies. Hydrogen sulfide (H2S) is a newly discovered endogenous small gas signaling molecule exerting a wide range of biologic actions in our body. This review illustrates recent experimental findings on the mechanisms underlying the therapeutic effects of H2S against renal fibrosis and highlights its potential in future clinical application. DATA SOURCES: Literature was collected from PubMed until February 2019, using the search terms including "Hydrogen sulfide," "Chronic kidney disease," "Renal interstitial fibrosis," "Kidney disease," "Inflammation factor," "Oxidative stress," "Epithelial-to-mesenchymal transition," "H2S donor," "Hypertensive kidney dysfunction," "Myofibroblasts," "Vascular remodeling," "transforming growth factor (TGF)-beta/Smads signaling," and "Sulfate potassium channels." STUDY SELECTION: Literature was mainly derived from English articles or articles that could be obtained with English abstracts. Article type was not limited. References were also identified from the bibliographies of identified articles and the authors' files. RESULTS: The experimental data confirmed that H2S is widely involved in various renal pathologies by suppressing inflammation and oxidative stress, inhibiting the activation of fibrosis-related cells and their cytokine expression, ameliorating vascular remodeling and high blood pressure, stimulating tubular cell regeneration, as well as reducing apoptosis, autophagy, and hypertrophy. Therefore, H2S represents an alternative or additional therapeutic approach for renal fibrosis. CONCLUSIONS: We postulate that H2S may delay the occurrence and progress of renal fibrosis, thus protecting renal function. Further experiments are required to explore the precise role of H2S in renal fibrosis and its application in clinical treatment.

5.
Int J Mol Sci ; 20(20)2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31614621

RESUMO

Cells of Microcystis are associated with heterotrophic bacteria and organized in colonies in natural environment, which are basic elements in the mass occurrence of cyanobacterial species. Analyzing these colonies by using metagenomics is helpful to understand species composition and relationship. Meanwhile, the difference in population abundance among Microcystis colonies could be used to recover genome bins from metagenome assemblies. Herein, we designed a pipeline to obtain high-quality genomes of mutualistic bacteria from single natural Microcystis colonies. Single colonies were lysed, and then amplified by using multiple displacement amplification to overcome the DNA quantity limit. A two-step assembly was performed after sequencing and scaffolds were grouped into putative bins based on their differential-coverage among species. We analyzed six natural colonies of three prevailing Microcystis species from Lake Taihu. Clustering results proved that colonies of the same species were similar in the microbial community composition. Eight putative population genome bins with wide bacterial diversity and different GC content were identified based on coverage difference among colonies. At the phylum level, proteobacteria was the most abundant besides cyanobacteria. Six of the population bins were further refined into nearly complete genomes (completeness > 90%).

6.
Micromachines (Basel) ; 10(10)2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31623361

RESUMO

Cell-free DNA (cfDNA), which promotes precision oncology, has received extensive concern because of its abilities to inform genomic mutations, tumor burden and drug resistance. The absolute quantification of cfDNA concentration has been proved as an independent prognostic biomarker of overall survival. However, the properties of low abundance and high fragmentation hinder the isolation and further analysis of cfDNA. Microfluidic technologies and lab-on-a-chip (LOC) devices provide an opportunity to deal with cfDNA sample at a micrometer scale, which reduces required sample volume and makes rapid isolation possible. Microfluidic platform also allow for high degree of automation and high-throughput screening without liquid transfer, where rapid and precise examination and quantification could be performed at the same time. Microfluidic technologies applied in cfDNA isolation and analysis are limited and remains to be further explored. This paper reviewed the existing and potential applications of microfluidic technologies in collection and enrichment of cfDNA, quantification, mutation detection and sequencing library construction, followed by discussion of future perspectives.

7.
Front Immunol ; 10: 1647, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379845

RESUMO

Background: Antibody-dependent cellular cytotoxicity (ADCC), which mainly mediated by natural killer (NK) cells, may play a critical role in human immunodeficiency virus type-1 (HIV-1) disease progression. However, the potential mechanisms that affecting NK-mediated ADCC response are still not well-elucidated. Methods: Antigen-antibody complex model of Ab-opsonized P815 cells was adopted to induce a typical non-specific ADCC response. The capacities of HIV-1 specific NK-ADCC were measured by using the combination model of gp120 protein and plasma of HIV-1 elite controllers. The levels of plasma cytokine were measured by ELISA. Anti-IL-2 blocking antibody was used to analyze the impact of activated CD56+ T cells on NK-ADCC response. Results: IL-2, IL-15, IFN-α, and IFN-ß could effectively enhance the non-specific and HIV-1-specific NK-ADCC responses. Compared with healthy controls, HIV-1-infected patients showed decreased plasma IL-2 levels, while no differences of plasma IFN-α, IL-15, and IFN-ß were presented. IL-2 production was detected from CD56+ T cells activated through antibody-dependent manner. The capability of NK-ADCC could be weakened by blocking IL-2 secretion from activated CD56+ T cells. Although no difference of frequencies of CD56+ T cells was found between HIV-1-infected patients and healthy controls, deficient IL-2 secretion from activated CD56+ T were found in chronic HIV-1 infection. Conclusions: The impaired ability of activated CD56+ T cells to secreting IL-2 might contribute to the attenuated NK cell-mediated ADCC function in HIV-1 infection.

8.
Int J Mol Sci ; 20(8)2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31010074

RESUMO

As the most widely-used single cell whole genome amplification (WGA) approach, multiple displacement amplification (MDA) has a superior performance, due to the high-fidelity and processivity of phi29 DNA polymerase. However, chimeric reads, generated in MDA, cause severe disruption in many single-cell studies. Herein, we constructed ChimeraMiner, an improved chimeric read detection pipeline for analyzing the sequencing data of MDA and classified the chimeric sequences. Two datasets (MDA1 and MDA2) were used for evaluating and comparing the efficiency of ChimeraMiner and previous pipeline. Under the same hardware condition, ChimeraMiner spent only 43.4% (43.8% for MDA1 and 43.0% for MDA2) processing time. Respectively, 24.4 million (6.31%) read pairs out of 773 million reads, and 17.5 million (6.62%) read pairs out of 528 million reads were accurately classified as chimeras by ChimeraMiner. In addition to finding 83.60% (17,639,371) chimeras, which were detected by previous pipelines, ChimeraMiner screened 6,736,168 novel chimeras, most of which were missed by the previous pipeline. Applying in single-cell datasets, all three types of chimera were discovered in each dataset, which introduced plenty of false positives in structural variation (SV) detection. The identification and filtration of chimeras by ChimeraMiner removed most of the false positive SVs (83.8%). ChimeraMiner revealed improved efficiency in discovering chimeric reads, and is promising to be widely used in single-cell sequencing.


Assuntos
Quimera/genética , Biologia Computacional/métodos , Software , Genoma Humano , Humanos , Análise de Célula Única , Sequenciamento Completo do Genoma
9.
Gene ; 699: 145-154, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30876822

RESUMO

BACKGROUND: Detecting heteroplasmic variations in the mitochondrial genome can help identify potential pathogenic possibilities, which is significant for disease prevention. The development of next-generation sequencing changed the quantification of mitochondrial DNA (mtDNA) heteroplasmy from scanning limited recorded points to the entire mitochondrial genome. However, due to the presence of nuclear mtDNA homologous sequences (nuMTs), maximally retaining real variations while excluding falsest heteroplasmic variations from nuMTs and sequencing errors presents a dilemma. RESULTS: Herein, we used an improved method for detecting low-frequency mtDNA heteroplasmic variations from whole genome sequencing data, including point variations and short-fragment length alterations, and evaluated the effect of this method. A two-step alignment was designed and performed to accelerate data processing, to obtain and retain the true mtDNA reads and to eliminate most nuMTs reads. After analyzing whole genome sequencing data of K562 and GM12878 cells, ~90% of heteroplasmic point variations were identified in MitoMap. The results were consistent with the results of an amplification refractory mutation system qPCR. Many linkages of the detected heteroplasmy variations were also discovered. CONCLUSIONS: Our improved method is a simple, efficient and accurate way to mine mitochondrial low-frequency heteroplasmic variations from whole genome sequencing data. By evaluating the highest misalignment possibility caused by the remaining nuMTs-like reads and sequencing errors, our procedure can detect mtDNA heteroplasmic variations whose heteroplasmy frequencies are as low as 0.2%.


Assuntos
Genoma Mitocondrial/genética , Mitocôndrias/genética , Mutação/genética , Linhagem Celular Tumoral , DNA Mitocondrial/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Células K562 , Análise de Sequência de DNA/métodos , Sequenciamento Completo do Genoma/métodos
10.
J Biomed Nanotechnol ; 15(5): 1106-1111, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30890240

RESUMO

In recent years, liquid-cell transmission electron microscopy (LC-TEM) has been developed as in-situ, dynamic characterization of nanoscale materials in the liquid, although the state-of-art focus is heavy materials such as metals, and alloys. Herein we present a practical and stable liquid cell fabricated with standard micro-electro-mechanical (MEM) processes on silicon wafers. The liquid cell is universal for commonly used TEM holder, which may not only keep the liquid available for several weeks, and it has been also proven protective factor from electron beam damage when characterizing biomolecules such as proteins and DNAs, which are typical light-element molecules. DNA polymerase has been successfully characterized in the physiological state (unlabeled in PBS buffer), providing single molecular resolution, the dynamic structural evolution of the molecules and the complex interactions. Although more understandings of this technique has to be explored in the future, as we have pointed out in the manuscript, this work has illustrated that the LC-TEM can also become a potential and promising strategy, besides to the cryo-TEM technique, in the high-resolution characterization of biomolecules, which may benefit relative researches and industry, such as molecular and structural biology, ecology, pharmacology and environmental sciences.


Assuntos
Nanotecnologia , DNA , DNA Polimerase Dirigida por DNA , Microscopia Eletrônica de Transmissão , Silício
11.
Nanotechnology ; 30(26): 26LT01, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-30836332

RESUMO

Freestanding graphene films are desired to be widely applied in biosensor fabrication due to their distinctive physical properties and improved performance. Chemical vapor deposition has been developed to efficiently fabricate large-area graphene. However, some of the fabricated graphene films might break or be contaminated in the current transferring step using polymers. A stable and high-quality transfer method is needed. Herein, we report on an advanced transfer method of large-area graphene film which uses fullerene as a supporting substrate. Unlike polymers, which are commonly eliminated by being dissolved in an organic solution, fullerene can be easily removed by evaporation in a vacuum because it has a different heat stability to graphene. By using the improved transferring method, the percentage of integrated freestanding films after transferring was increased from 60.7% to 93.4%. The vacuum is beneficial in terms of keeping the brittle freestanding films intact. Graphene films transferred using fullerene showed an advanced flatness and a simplicial elementary composition in comparison to those transferred using polymers. Even through there is trace residue, this stable allotrope of graphene is considered to have almost no impact on biomolecule sensing. These advantages make the fullerene transferring method an attractive candidate for fabricating large-area freestanding graphene films, especially for using in the field of biochemistry analysis and biosensors.

12.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 37(1): 76-80, 2019 Feb 01.
Artigo em Chinês | MEDLINE | ID: mdl-30854824

RESUMO

OBJECTIVE: We aim to examine teenagers with varying vertical facial skeletal types with near-normal occlusion. We further aim to identify and study mandibular morphology and dentition characteristics to establish normal ranges and variations for future clinical reference. METHODS: According to the results of the case studies, 42 adolescents with near-normal occlusion were divided into three groups, namely, low- (7 cases), average- (23 cases) and high-angle (12 cases) groups. We used Invivo 5 software for Digital Imaging and Communications in Medicine (DICOM) data to calculate the cant of occlusal plane, axis corner of L6, ∠L1/MP, ∠L6/MP, Balkwill angle and Bonwill triangle of each group. RESULTS: Markedly, the finding shows that the cant of occlusal plane and axis corner of L6 in the low-angle group were smaller than those of the other two groups. In the average-angle group, ∠L1/MP was larger than that of the high-angle group. Lastly, in the high-angle group, ∠L6/MP was smaller than those of the two other groups. On the one hand, these differences were considered statistically significant (P<0.05). On the other hand, other measurements show that these differences were considered statistically non-significant (P>0.05). CONCLUSIONS: In the low-angle group, the parallelisation of the occlusal plane tends to be more obvious compared with the two other groups. In the coronal section of the low-angle group, the axis of the mandibular first molar is up-right, whereas it is distally tilted in the sagittal section of the high-angle group. Furthermore, a number of differences are noted in the adult groups. Factors, such as aging and development in the craniofacial region, lead to changes in functional occlusion.


Assuntos
Cefalometria , Oclusão Dentária , Dentição , Adolescente , Humanos , Mandíbula , Dente
13.
J Biomol Struct Dyn ; 37(11): 2970-2979, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30058436

RESUMO

Bromodomain-containing protein 9 (BRD9) has been employed as a potential target for anticancer drugs in recent years. In this work, molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and per residue energy decomposition approaches were performed to elucidate the different binding modes between four pyridinone-like scaffold inhibitors and BRD9 bromodomain. Analysis results indicate that non-polar contribution mainly deriving from van der Waals energy is a critical impact on binding affinity of inhibitors against BRD9. Some key residues Phe44, Phe47, Val49, and Ile53 (at ZA loop) enhance the binding energy of inhibitors in BRD9 by means of providing hydrophobic interactions. Moreover, it is observed that BRD9 is anchored by the formation of a stable hydrogen bond between the carbonyl of the inhibitors and the residue Asn100 (at BC loop), and a strong π-π stacking interaction formed between the residue Tyr106 (at BC loop) and the inhibitors. The existence of dimethoxyphenyl structure and the aromatic ring merged to pyridinone scaffold are useful to enhance the BRD9 binding affinity. These findings should guide the rational design of more prospective inhibitors targeting BRD9. Communicated by Ramaswamy H. Sarma.

14.
J Cell Biochem ; 120(1): 562-574, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30191596

RESUMO

As a potent and selective drug, brigatinib exhibits high efficacy against wild-type and mutant anaplastic lymphoma kinase (ALK) proteins to treat non-small cell lung cancer. In this work, the mechanisms of brigatinib binding to wild type and four mutant ALKs were investigated to gain insight into the dynamic energetic and structural information with respect to the design of novel inhibitors. Comparison between ALK-brigatinib and ALK-crizotinib suggests that the scaffold of brigatinib is well anchored to the residue Met1199 of hinge region by two hydrogen bonds, and the residue Lys1150 has the strong electrostatic interaction with the dimethylphosphine oxide moiety in brigatinib. These ALK mutations have significant influences on the flexibility of P-loop region and DFG sequences, but do not impair the hydrogen bonds between brigatinib and the residue Met1199 of hinge region. And mutations (L1196M, G1269A, F1174L, and R1275Q) induce diverse conformational changes of brigatinib and the obvious energy variation of residues Glu1167, Arg1209, Asp1270, and Asp1203. Together, the detailed explanation of mechanisms of those mutations with brigatinib further provide several guidelines for the development of more effective ALK inhibitors.

15.
J Biomol Struct Dyn ; 37(11): 2913-2925, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30044186

RESUMO

Tuberculosis (TB) is an infectious disease that causes a number of deaths, and the development of new, safer and more adequate TB inhibitors/drugs has become a necessity as well as a great challenge. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially underexploited drug targets in the field of anti-tubercular drug discovery. To design the novel and potent Mycobacterium tuberculosis (MTB) inhibitors, we performed molecular modeling studies that combined the 3D-QSAR, molecular docking, molecular dynamics (MD) simulations, and binding free energy calculations. Forty eight quinoline-aminopiperidine inhibitors which act on DNA gyrase B subunit were used for constructing 3D-QSAR models. The results showed that the best CoMFA model had the high performance with q2 = 0.643, r2 = 0.947, while the best CoMSIA model yielded q2 = 0.536, r2 = 0.948. The contour map was in good agreement with the docking and MD simulations which strongly demonstrated that the molecular modeling was reliable. Based on this information, several potential compounds were designed and their inhibitory activities were also verified by the accomplished models and ADME/T predictions. We hope that our research could bring new ideas to facilitate the development of novel inhibitors with higher inhibitory activity for TB. Communicated by Ramaswamy H. Sarma.

16.
Nanoscale ; 10(37): 17933-17941, 2018 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-30226245

RESUMO

Whole genome amplification (WGA) has laid the foundation for investigating complex genomic alteration with single-cell or even single-molecule resolution. Coupled with sequencing-based copy number variation (CNV) analysis, it promotes understanding of the nature of commonly existing genetic heterogeneity by constructing the sequencing profiles for every single cell. However, prevailing methods only provide insights into limited aspects due to their intrinsic technical challenges. Their output data, as a result, fails to render comprehensive information (which is) concerned. Here, we describe the CNV detection analysis based on micro-channel multiple displacement amplification (µcMDA), a protocol able to provide optimized amplification uniformity while inheriting the advantages of MDA chemistry. We demonstrate the analysis of both the normal diploid YH-1 cell line and the aneuploid K562 cancer cell line. In the detection of simulated CNVs ranging from 300 kb to 2 Mb, µcMDA can respectively increase the detection rates of copy number loss and gain by 28.8% and 40.2% on average, using only 0.2× sequencing data. When detecting the inherent CNVs in tumor cells, the resolution of CNV recognition can be improved to 250 kb. Starting from either superabundant template copies or minute single-cell-level input, this easily accessible approach is capable of providing quantitatively reliable coverage as well as more robust GC-content regression for CNV detection.


Assuntos
Variações do Número de Cópias de DNA , Técnicas de Amplificação de Ácido Nucleico , Aneuploidia , Composição de Bases , Linhagem Celular , Genoma Humano , Humanos , Células K562
17.
Oncol Lett ; 16(4): 4863-4870, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30250552

RESUMO

Gastric cancer is a highly heterogeneous disease and the second leading cause of cancer-associated mortality. However, the genomic basis of gastric cancer is not completely understood and the underlying genetic heterogeneity has not been well studied. In the present study, 1,021 genes were sequenced and the somatic mutations of 45 formalin-fixed, paraffin-embedded gastric adenocarcinoma samples were assessed using next-generation sequencing technologies. In the present study, a median sequencing coverage depth of 708-fold was achieved. Somatic genomic alterations were detected in 37/45 patients (82.4%) and the most frequent genetic alterations identified were tumor protein P53 (TP53) gene mutations. Mutations in MLL4, ERBB3, FBXW7, MLL3, MTOR, NOTCH1, PIK3CA, KRAS, ERBB4 and EGFR were also detected. Patients with TP53 mutations had a higher number of somatic mutations, and the total number of somatic mutations was weakly correlated with patient age. These results provided data on the intratumoral heterogeneity of gastric cancer and may be used in order to develop personalized cancer therapy.

18.
Bioanalysis ; 10(15): 1177-1180, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30136900
19.
Int J Biol Macromol ; 118(Pt A): 1149-1156, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30001602

RESUMO

As an attractive therapeutic target for non-small-cell lung cancer (NSCLC), anaplastic lymphoma kinase (ALK) has got increased attention, and the selectivity of ALK inhibitors is an enormous challenge. Recently, 2,4-Diarylaminopyrimidines with high inhibitory activity over InsR/IGF1R were reported as ALK inhibitors, which harboring phosphine oxide moiety. In this work, it is the first time to reveal that the incorporation of dimethylphosphine oxide moiety and the smaller active pocket of ALK is key factor in the selectivity of inhibitor 11q toward ALK over IGF1R/InsR. The results of molecular simulation indicate that the subtle change in the binding pocket of ALK is mainly associated with the flexibility of P-loop and the own residues K1150 and D1270. The replacement of the dimethylphosphine oxide and methylpiperazine of inhibitor 11q would alter the major inhibitory effects of binding and activation. The results further combined 3D-QSAR can not only profile the binding mechanism between the 2,4-Diarylaminopyrimidines inhibitors and ALK, but also supply the useful information for the rational design of a more potential small molecule inhibitor bound to ALK receptor.


Assuntos
Desenho de Drogas , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/enzimologia , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/enzimologia , Receptores Proteína Tirosina Quinases/química
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