Chemical-Shift Perturbations Reflect Bile Acid Binding to Norovirus Coat Protein: Recognition Comes in Different Flavors

Bile acids have been reported as important cofactors promoting human and murine norovirus (NoV) infections in cell culture. The underlying mechanisms are not resolved. Through the use of chemical shift perturbation (CSP) NMR experiments, we identified a low-affinity bile acid binding site of a human GII.4 NoV strain. Long-timescale MD simulations reveal the formation of a ligand-accessible binding pocket of flexible shape, allowing the formation of stable viral coat protein–bile acid complexes in agreement with experimental CSP data. CSP NMR experiments also show that this mode of bile acid binding has a minor influence on the binding of histo-blood group antigens and vice versa. STD NMR experiments probing the binding of bile acids to virus-like particles of seven different strains suggest that low-affinity bile acid binding is a common feature of human NoV and should therefore be important for understanding the role of bile acids as cofactors in NoV infection.     

New 1,3,4-Oxadiazole Derivatives of Pyridothiazine-1,1-Dioxide with Anti-Inflammatory Activity

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.     

Genes Identification,Molecular Docking and Dynamics Simulation Analysis of Laccases from Amylostereum areolatum Provides Molecular Basis of Laccase Bound to Lignin

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.     

伪码连续波交会对接雷达信号处理机设计

介绍了某伪码连续波交会对接雷达信号处理机设计.在测距中,提出用噪声较小的载波相位△伪距测量值对伪距进行处理,得到高精度测距值.在测角中,提出了一种干涉仪天线阵结构和干涉仪解模糊算法,针对通道载波相位误差可能引起的解模糊错误,又提出了一种纠正方法,仿真显示,在发生解模糊错误的概率高达0.42的情况下,该方法仍然可以识别并纠正所有解模糊错误.实验表明,该信号处理机可以满足空间航天器交会对接的要求.     

空间交会对接用激光雷达敏感器

本文讨论了在航天飞行器的空间交会对接(RVD)技术中采用激光雷达敏感器的可行性。提出在航天飞行器的自主交会对接技术中,应采用一种简单、实用的单目标系统。     

火星探测器转移轨道的自主导航方法

本文针对转移轨道火星探测器对自主导航的迫切需求,提出了一种基于小行星和X射线脉冲星交互观测的自主导航方法,并结合工程任务对上述量测信息的获取方式和获取条件进行了研究,仿真结果表明,与单独基于小行星或单独基于X射线脉冲星观测的自主导航系统相比,该方法不仅可获得更高的导航精度,为转移轨道中途修正提供准确的轨道信息,且工程实现简单,是一种可行的转移轨道火星探测器自主导航方案,可为我国火星探测器自主导航系统的设计提供参考.     

Secondary Metabolic Profile as a Tool for Distinction and Characterization of Cultivars of Black Pepper (Piper nigrum L.) Cultivated in Pará State,Brazil

This study evaluated the chemical compositions of the leaves and fruits of eight black pepper cultivars cultivated in Pará State (Amazon, Brazil). Hydrodistillation and gas chromatography–mass spectrometry were employed to extract and analyze the volatile compounds, respectively. Sesquiterpene hydrocarbons were predominant (58.5–90.9%) in the cultivars “Cingapura”, “Equador”, “Guajarina”, “Iaçará”, and “Kottanadan”, and “Bragantina”, “Clonada”, and “Uthirankota” displayed oxygenated sesquiterpenoids (50.6–75.0%). The multivariate statistical analysis applied using volatile composition grouped the samples into four groups: γ-Elemene, curzerene, and δ-elemene (“Equador”/“Guajarina”, I); δ-elemene (“Iaçará”/“Kottanadan”/“Cingapura”, II); elemol (“Clonada”/“Uthirankota”, III) and α-muurolol, bicyclogermacrene, and cubebol (“Bragantina”, IV). The major compounds in all fruit samples were monoterpene hydrocarbons such as α-pinene, β-pinene, and limonene. Among the cultivar leaves, phenolics content (44.75–140.53 mg GAE·g⁻¹ FW), the enzymatic activity of phenylalanine-ammonia lyase (20.19–57.22 µU·mL⁻¹), and carotenoids (0.21–2.31 µg·mL⁻¹) displayed significant variations. Due to black pepper’s susceptibility to Fusarium infection, a molecular docking analysis was carried out on Fusarium protein targets using each cultivar’s volatile components. F. oxysporum endoglucanase was identified as the preferential protein target of the compounds. These results can be used to identify chemical markers related to the susceptibility degree of black pepper cultivars to plant diseases prevalent in Pará State.     

Molecular Docking Studies and Biological Evaluation of Berberine–Benzothiazole Derivatives as an Anti-Influenza Agent via Blocking of Neuraminidase

In this study, we have introduced newly synthesized substituted benzothiazole based berberine derivatives that have been analyzed for their in vitro and in silico biological properties. The activity towards various kinds of influenza virus strains by employing the cytopathic effect (CPE) and sulforhodamine B (SRB) assay. Several berberine–benzothiazole derivatives (BBDs), such as BBD1, BBD3, BBD4, BBD5, BBD7, and BBD11, demonstrated interesting anti-influenza virus activity on influenza A viruses (A/PR/8/34, A/Vic/3/75) and influenza B viral (B/Lee/40, and B/Maryland/1/59) strain, respectively. Furthermore, by testing neuraminidase activity (NA) with the neuraminidase assay kit, it was identified that BBD7 has potent neuraminidase activity. The molecular docking analysis further suggests that the BBD1–BBD14 compounds’ antiviral activity may be because of interaction with residues of NA, and the same as in oseltamivir.     

AKT Inhibitors: The Road Ahead to Computational Modeling-Guided Discovery

AKT, is a serine/threonine protein kinase comprising three isoforms—namely: AKT1, AKT2 and AKT3, whose inhibitors have been recognized as promising therapeutic targets for various human disorders, especially cancer. In this work, we report a systematic evaluation of multi-target Quantitative Structure-Activity Relationship (mt-QSAR) models to probe AKT’ inhibitory activity, based on different feature selection algorithms and machine learning tools. The best predictive linear and non-linear mt-QSAR models were found by the genetic algorithm-based linear discriminant analysis (GA-LDA) and gradient boosting (Xgboost) techniques, respectively, using a dataset containing 5523 inhibitors of the AKT isoforms assayed under various experimental conditions. The linear model highlighted the key structural attributes responsible for higher inhibitory activity whereas the non-linear model displayed an overall accuracy higher than 90%. Both these predictive models, generated through internal and external validation methods, were then used for screening the Asinex kinase inhibitor library to identify the most potential virtual hits as pan-AKT inhibitors. The virtual hits identified were then filtered by stepwise analyses based on reverse pharmacophore-mapping based prediction. Finally, results of molecular dynamics simulations were used to estimate the theoretical binding affinity of the selected virtual hits towards the three isoforms of enzyme AKT. Our computational findings thus provide important guidelines to facilitate the discovery of novel AKT inhibitors.