靶向抑制DNA拓扑异构酶的抗肿瘤药物研究

DNA拓扑异构酶是真核细胞和原核细胞中的一种基本酶,广泛存在于细胞核中,对DNA的转录、复制以及基因表达过程中的DNA拓扑结构的改变起着重要的作用。研究发现DNA拓扑异构酶在肿瘤组织中高度表达,许多抗肿瘤药物的作用机制与抑制拓扑异构酶有关,目前拓扑异构酶已成为筛选抗肿瘤药物的重要靶点。     

3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

Structural modifications of 3-OH in the glucose moiety of dapagliflozin（1）, an approved potent sodium-dependent glucose transporter 2（SGLT2） inhibitor, led to 3-oxodapagliflozin（16）, a highly potent and more selective SGLT2 inhibitor[IC50（hSGLT1）/IC50（hSGLT2）=2851 for compound 16 vs. 843 for compound 1]. 3-Oxodapagliflozin（16） exhibited in vitro（IC50=1.0nmol/L against hSGLT2 for compound 16 vs. 1.3 nmol/L for compound 1） and in vivo activities comparable to those of dapagliflozin（1）. The bioactivities of 3-oxodapagliflozin （16） warrant its further evaluation as a promising SGLT2 inhibitor for the treatment of type 2 diabetes.     

A Biomimetic Nanoparticle to “Lure and Kill” Phospholipase A2

Inhibition of phospholipase A2 (PLA2) has long been considered for treating various diseases associated with an elevated PLA2 activity. However, safe and effective PLA2 inhibitors remain unavailable. Herein, we report a biomimetic nanoparticle design that enables a “lure and kill” mechanism designed for PLA2 inhibition (denoted “L&K-NP”). The L&K-NPs are made of polymeric cores wrapped with modified red blood cell membrane with two inserted key components: melittin and oleyloxyethyl phosphorylcholine (OOPC). Melittin acts as a PLA2 attractant that works together with the membrane lipids to “lure” in-coming PLA2 for attack. Meanwhile, OOPC acts as inhibitor that “kills” PLA2 upon enzymatic attack. Both compounds are integrated into the L&K-NP structure, which voids toxicity associated with free molecules. In the study, L&K-NPs effectively inhibit PLA2-induced hemolysis. In mice administered with a lethal dose of venomous PLA2, L&K-NPs also inhibit hemolysis and confer a significant survival benefit. Furthermore, L&K-NPs show no obvious toxicity in mice. and the design provides a platform technology for a safe and effective anti-PLA2 approach.     

通过FGF401的构效关系研究发现一种新颖的FGFR4选择性抑制剂

设计并合成了一系列FGF401类似物以研究其FGFR4抑制、抗肿瘤活性及其构效关系.研究发现了N-(5-氰基-4-(2-甲氧基乙基氨基)吡啶-2-基)-7-甲酰基-6-(N-甲基四氢吡喃-4-甲酰胺)甲基-1,2,3,4-四氢-1,8-萘啶-1-甲酰胺(8ac)不仅在酶和细胞学水平上对FGFR4具有强效的的抑制活性,并表现出了出色的选择性.其活性及选择性优于阳性对照FGF401,并且在HCC (hepatocellular carcinoma)动物移植瘤模型中显著抑制肿瘤生长,还引起了肿瘤萎缩.     

Different defect morphologies in polyethylene crystal induced by surface physicochemical properties

The physicochemical properties of surfaces have a great effect on the micro-morphologies of the crystal structures which are in contact with them.Understanding the interaction mechanism between the internal driving forces of the crystal and external inducing forces of the surfaces is the prerequisite of controlling and obtaining the desirable morphologies.In this work,the dynamic density functional theory was applied to construct the free energy functional expression of polyethylene(PE) lattice,and the micro-dynamic evolution processes of PE lattice morphology near the surfaces with different properties were observed to reveal the interaction mechanism at atomic scale.The results showed that the physical and chemical properties of the external surfaces synergistically affect the morphologies in both the defect shapes and the distribution of the defect regions.In the absence of the contact surfaces,driven by the oriented interactions among different CH2 groups,PE lattices gradually grow and form a defect-free structure.Conversely,the presence of contact surfaces leads to lattice defects in the interfacial regions,and PE lattice shows different self-healing abilities around different surfaces.     

Demystifying terms for understanding bioelectrochemical systems towards sustainable wastewater treatment

Bioelectrochemical systems (BESs) have been intensively studied in the past decade, but precise understanding of BESs performance is hindered by unclear definition of several key parameters. Herein, we analyze and discuss three sets of terms about conversion efficiency, energy performance, and pilot scale. It is suggested that ‘Coulombic recovery’ can avoid the misleading results because of different organic removals, compared with ‘Coulombic efficiency.’ Power density is not a suitable term to describe energy performance of BESs, and energy production/consumption should be reported in the energy unit such as kWh. Pilot-scale BESs should meet several criteria, including hydraulic capacity, use of actual wastewater, non-laboratory condition, and long-term operation. Proper use of those terms is strongly encouraged and will be critically important to BESs research and development.     

Structure-based virtual screening of natural products as potential stearoyl-coenzyme a desaturase 1 (SCD1) inhibitors

Stearyl coenzyme A desaturase enzyme 1 (SCD1) is a key enzyme that catalyzes the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA) and plays a vital role in lipid metabolism of tumor cells. SCD1 is overexpressed in a variety of malignant tumors, and its related inhibitors showed significant anti-tumor activity in vitro and in vivo experiments, which is a new target for tumor therapy. The focus of this study is to identify novel SCD1 inhibitors from natural products through computer simulations. First, 176,602 compounds from natural product databases were virtually screened. By molecular dynamics (MD) simulations, the ligand-protein interactions of 5 compounds with high docking manifestation were analyzed accurately. Then, MM-GBSA and MM-PBMA methods were used to verify the results. Finally, ADMET prediction was performed for the 5 compounds. As a result, two natural products with potential inhibition towards SCD1 were identified, which had the excellent docking manifestation, binding mode within SCD1 pocket and stability during molecular dynamics simulation. This study provides a meaningful model for the development and optimization of new inhibitors and anti-tumor drugs targeting SCD1.     

Structure-based virtual screening of influenza virus RNA polymerase inhibitors from natural compounds: Molecular dynamics simulation and MM-GBSA calculation

The resistances of matrix protein 2 (M2) protein inhibitors and neuraminidase inhibitors for influenza virus have attracted much attention and there is an urgent need for new drug. The antiviral drugs that selectively act on RNA polymerase are less prone to resistance and possess fewer side effects on the patient. Therefore, there is increased interest in screening compounds that can inhibit influenza virus RNA polymerase. Three natural compounds were found by using molecular docking-based virtual screening, which could bind tightly within the polymerase acidic protein-polymerase basic protein 1 (PA-PB1) subunit of influenza virus polymerase. Firstly, their drug likeness properties were evaluated, which showed that the hepatotoxicity values of all the three compounds indicating they had less or no hepatotoxicity, and did not have the plasma protein biding (PPB) ability, the three compounds needed to be modified in some aspects, like bulky molecular size. The stability of the complexes of PA-hits was validated through molecular dynamics (MD) simulation, revealing compound 2 could form more stable complex with PA subunit. The torsional conformations of each rotatable bond of the ligands in PA subunit were also monitored, to investigate variation in the ligand properties during the simulation, compound 3 had fewer rotatable bonds, indicating that the molecule had stronger rigidity. The bar charts of protein–ligand contacts and contacts over the course of trajectory showed that four key residues (Glu623, Lys643, Asn703 and Trp706) of PA subunit that participated in hydrogen-bond, water bridge and hydrophobic interactions with the hit compounds. Finally, the binding free energy and contributed energies were calculated by using MM-GBSA method. Out of the three compounds, compound 1 showed the lowest total binding free energy. Among all the interactions, the contribution of the covalent binding and the van der Waals energy were more than other items, compound 1 formed more stable hydrogen bonds with the residues of PA subunit binding pocket. This study smoothed the path for the development of novel lead compounds with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of influenza, which provided a good basis for further research on novel and effective influenza virus PA-PB1 interaction inhibitors.     

硫化丁苯橡胶纳观界面耐磨机理及参数影响分析

硫化橡胶因其良好的力学和物理化学性能而被广泛作为摩擦副的基础材料. 本文提出了一种硫化交联算法, 实现了C—C键的硫化互交联和自交联, 构建了硫化丁苯橡胶的分子动力学磨损模型, 从微观摩擦学的角度阐明了硫化交联结构对改善丁苯橡胶磨损性能的机理, 研究了不同界面参数对硫化橡胶微观磨损性能的影响. 结果发现 硫化使丁苯橡胶分子链的界面黏附能力和活动能力更弱, 拉伸和解缠能力更低, 磨损过程中界面累积能量更低, 更不容易脱离橡胶基体, 因此可以表现出更好的摩擦学性能, 更强的抗磨损性能; 随着速度的增大, 硫化橡胶的磨损率降低, 与宏观实验结果一致, 原因是硫化橡胶的原子分布函数和相互作用能随着速度增大而降低, 说明橡胶分子链的黏附能力和活动能力随着速度增加趋弱, 温升更低, 导致较低的磨损率; 压入深度对磨损率的影响规律则呈现相反的结果和趋势.     

In Vitro Anti-Diabetic Activities and UHPLC-ESI-MS/MS Profile of Muntingia calabura Leaves Extract

Anti-diabetic compounds from natural sources are now being preferred to prevent or treat diabetes due to adverse effects of synthetic drugs. The decoction of Muntingia calabura leaves was traditionally consumed for diabetes treatment. However, there has not been any published data currently available on the processing effects on this plant’s biological activity and phytochemical profile. Therefore, this study aims to evaluate the effect of three drying methods (freeze-drying (FD), air-drying (AD), and oven-drying (OD)) and ethanol:water ratios (0, 50, and 100%) on in vitro anti-diabetic activities of M. calabura leaves. In addition, an ultrahigh-performance-liquid chromatography–electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) method was used to characterize the metabolites in the active extract. The FD M. calabura leaves, extracted with 50% ethanol, is the most active extract that exhibits a high α-glucosidase and α-amylase inhibitory activities with IC₅₀ values of 0.46 ± 0.05 and 26.39 ± 3.93 µg/mL, respectively. Sixty-one compounds were tentatively identified by using UHPLC-ESI-MS/MS from the most active extract. Quantitative analysis, by using UHPLC, revealed that geniposide, daidzein, quercitrin, 6-hydroxyflavanone, kaempferol, and formononetin were predominant compounds identified from the active extract. The results have laid down preliminary steps toward developing M. calabura leaves extract as a potential source of bioactive compounds for diabetic treatment.