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11.
Maria Rita Gulotta Serena Vittorio Rosaria Gitto Ugo Perricone Laura De Luca 《International journal of molecular sciences》2021,22(4)
The modulation of protein-protein interactions (PPIs) by small molecules represents a valuable strategy for pharmacological intervention in several human diseases. In this context, computer-aided drug discovery techniques offer useful resources to predict the network of interactions governing the recognition process between protein partners, thus furnishing relevant information for the design of novel PPI modulators. In this work, we focused our attention on the MUC1-CIN85 complex as a crucial PPI controlling cancer progression and metastasis. MUC1 is a transmembrane glycoprotein whose extracellular domain contains a variable number of tandem repeats (VNTRs) regions that are highly glycosylated in normal cells and under-glycosylated in cancer. The hypo-glycosylation fosters the exposure of the backbone to new interactions with other proteins, such as CIN85, that alter the intracellular signalling in tumour cells. Herein, different computational approaches were combined to investigate the molecular recognition pattern of MUC1-CIN85 PPI thus unveiling new structural information useful for the design of MUC1-CIN85 PPI inhibitors as potential anti-metastatic agents. 相似文献
12.
Alison Jee Samantha Christine Sernoskie Jack Uetrecht 《International journal of molecular sciences》2021,22(6)
Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses. 相似文献
13.
Adele Boccuto Filippo Dragoni Francesca Picarazzi Alessia Lai Carla Della Ventura Carla Veo Federica Giammarino Francesco Saladini Gianguglielmo Zehender Maurizio Zazzi Mattia Mori Ilaria Vicenti 《International journal of molecular sciences》2021,22(5)
The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC50) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC50 shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development. 相似文献
14.
Luo Xin Yufeng Zhang Wenshan Duan Mingyan Ai Hongbo Song Qun Huang Jiankang Lu 《International Journal of Food Science & Technology》2022,57(5):2646-2655
Oil, accounting for 45% of almonds, is easily oxidised and can further induce the protein oxidation to reduce their quality. Structure and physicochemical properties of amandin, the main water-soluble protein in almonds, inducing oxidation by malondialdehyde (MDA) were investigated. The results showed that the content of carbonyl group increased from 5.23 to 33.25 nmol mg−1 of protein with the increase in MDA concentration (P < 0.05). However, the sulphydryl content, surface hydrophobicity, particle size and the absolute value of ζ-potential first increased and then decreased. Fourier-transformed infrared spectroscopy (FT-IR) confirmed that the structure of amandin changed from order to disorder. Fluorescence spectroscopic analysis revealed that mild oxidation (0–0.1 mmol L−1 MDA) exposed hydrophobic groups of the protein. Sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) suggested that protein oxidation promoted crosslinking between protein molecules. Furthermore, protein oxidation markedly declined the total amino acid content of amandin (P < 0.05). In conclusion, MDA oxidation changed the structure and amino acid content of amandin, and caused the protein aggregate and crosslink through hydrophobic interaction and electrostatic interaction. 相似文献
15.
16.
Cristina Di Carluccio Enrique Crisman Prof. Yoshiyuki Manabe Rosa Ester Forgione Dr. Alessandra Lacetera Dr. Jussara Amato Dr. Bruno Pagano Prof. Antonio Randazzo Prof. Angela Zampella Prof. Rosa Lanzetta Prof. Koichi Fukase Prof. Antonio Molinaro Prof. Paul R. Crocker Prof. Sonsoles Martín-Santamaría Dr. Roberta Marchetti Prof. Alba Silipo 《Chembiochem : a European journal of chemical biology》2020,21(1-2):129-140
CD22 (Siglec-2) is a B-cell surface inhibitory protein capable of selectively recognising sialylated glycans, thus dampening autoimmune responses against self-antigens. Here we have characterised the dynamic recognition of complex-type N-glycans by human CD22 by means of orthogonal approaches including NMR spectroscopy, computational methods and biophysical assays. We provide new molecular insights into the binding mode of sialoglycans in complex with h-CD22, highlighting the role of the sialic acid galactose moieties in the recognition process, elucidating the conformational behaviour of complex-type N-glycans bound to Siglec-2 and dissecting the formation of CD22 homo-oligomers on the B-cell surface. Our results could enable the development of additional therapeutics capable of modulating the activity of h-CD22 in autoimmune diseases and malignancies derived from B-cells. 相似文献
17.
Teresa Glomb Benita Wiatrak Katarzyna Gbczak Tomasz Gbarowski Dorota Bodetko aneta Czynikowska Piotr
witek 《International journal of molecular sciences》2020,21(23)
Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases. 相似文献
18.
Priyadarshi Chakraborty Yiming Tang Tomoya Yamamoto Yifei Yao Tom Guterman Shai Zilberzwige-Tal Nofar Adadi Wei Ji Tal Dvir Ayyalusamy Ramamoorthy Guanghong Wei Ehud Gazit 《Advanced materials (Deerfield Beach, Fla.)》2020,32(9):1906043
Self-assembled peptide hydrogels represent the realization of peptide nanotechnology into biomedical products. There is a continuous quest to identify the simplest building blocks and optimize their critical gelation concentration (CGC). Herein, a minimalistic, de novo dipeptide, Fmoc-Lys(Fmoc)-Asp, as an hydrogelator with the lowest CGC ever reported, almost fourfold lower as compared to that of a large hexadecapeptide previously described, is reported. The dipeptide self-assembles through an unusual and unprecedented two-step process as elucidated by solid-state NMR and molecular dynamics simulation. The hydrogel is cytocompatible and supports 2D/3D cell growth. Conductive composite gels composed of Fmoc-Lys(Fmoc)-Asp and a conductive polymer exhibit excellent DNA binding. Fmoc-Lys(Fmoc)-Asp exhibits the lowest CGC and highest mechanical properties when compared to a library of dipeptide analogues, thus validating the uniqueness of the molecular design which confers useful properties for various potential applications. 相似文献
19.
Ningning Fu Jiaxing Li Ming Wang Lili Ren Youqing Luo 《International journal of molecular sciences》2020,21(22)
An obligate mutualistic relationship exists between the fungus Amylostereum areolatum and woodwasp Sirex noctilio. The fungus digests lignin in the host pine, providing essential nutrients for the growing woodwasp larvae. However, the functional properties of this symbiosis are poorly described. In this study, we identified, cloned, and characterized 14 laccase genes from A. areolatum. These genes encoded proteins of 508 to 529 amino acids and contained three typical copper-oxidase domains, necessary to confer laccase activity. Besides, we performed molecular docking and dynamics simulation of the laccase proteins in complex with lignin compounds (monomers, dimers, trimers, and tetramers). AaLac2, AaLac3, AaLac6, AaLac8, and AaLac10 were found that had low binding energies with all lignin model compounds tested and three of them could maintain stability when binding to these compounds. Among these complexes, amino acid residues ALA, GLN, LEU, PHE, PRO, and SER were commonly present. Our study reveals the molecular basis of A. areolatum laccases interacting with lignin, which is essential for understanding how the fungus provides nutrients to S. noctilio. These findings might also provide guidance for the control of S. noctilio by informing the design of enzyme mutants that could reduce the efficiency of lignin degradation. 相似文献
20.
采用显微组织分析和分子动力学模拟等方法研究了退火温度对0Cr25Al5热轧态盘条钢组织及性能的影响。结果发现,晶粒尺寸随温度的升高逐渐增加并趋于稳定,但是断后伸长率和断面收缩率在950 ℃突然大幅度下降。试样组织形貌在800 ℃和950 ℃退火温度下的OM及SEM分析结果未见明显差别。于是使用分子动力学模拟对0Cr25Al5钢三元体系的自由能进行了计算,发现随着B2结构的FeAl或者DO3结构的Fe3Al有序相尺寸的增大,系统自由能先减小后增大,其最小值随着退火温度的升高向有序相颗粒尺寸减小的方向移动。在1273 K的高温下仍然会保留60 nm左右大小的有序相颗粒。因此,推测0Cr25Al5钢在大于950 ℃的温度范围内韧性下降是由于60 nm左右的B2结构的FeAl或者DO3结构的Fe3Al有序相造成,与晶粒尺寸无关。因此,针对该钢种应进行低温退火促使基体组织回复以消除缺陷,从而抑制Fe、Al等基体原子的扩散。 相似文献