Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer.     

Experimental and numerical investigations on the heat production and thermal storage characteristics of rapid preparation amorphous powder activated coke

The heat production and thermal storage characteristics of rapid-preparation amorphous powder activated coke (RAC) were investigated. RAC was prepared by using a drop-tube reactor system. The natural oxidation characteristics of RAC were studied through combined TG–FTIR analysis and temperature-programmed experiment. Experimental results showed that CO and CO₂ were the main oxidation products of RAC in air, and that the oxidation reaction was in accordance with the Arrhenius equation and law of mass action. Thermal storage characteristics were studied through computational fluid dynamics simulation. The maximum excess temperature θ_max increases linearly with the increase of the initial temperature. The concentration fields of the products show that CO₂ is mainly concentrated in the upper part of the coke bin, and the CO generated by CO₂ at high temperature is mainly concentrated in the central part of the coke bin.     

A Structure−Activity Relationship Study of Novel Hydroxamic Acid Inhibitors around the S1 Subsite of Human Aminopeptidase N

Aminopeptidase N (APN/CD13) is a zinc-dependent ubiquitous transmembrane ectoenzyme that is widely present in different types of cells. APN is one of the most extensively studied metalloaminopeptidases as an anti-cancer target due to its significant role in the regulation of metastasis and angiogenesis. Previously, we identified a potent and selective APN inhibitor, N-(2-(Hydroxyamino)-2-oxo-1-(3′,4′,5′-trifluoro-[1,1′-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide ( 3 ). Herein, we report the further modifications performed to explore SAR around the S1 subsite of APN and to improve the physicochemical properties. A series of hydroxamic acid analogues were synthesised, and the pharmacological activities were evaluated in vitro. N-(1-(3′-Fluoro-[1,1′-biphenyl]-4-yl)-2-(hydroxyamino)-2-oxoethyl)-4-(methylsulfonamido)benzamide ( 6 f ) was found to display an extremely potent inhibitory activity in the sub-nanomolar range.     

Two Methods,One Goal: Structural Differences between Cocrystallization and Crystal Soaking to Discover Ligand Binding Poses

In lead optimization, protein crystallography is an indispensable tool to analyze drug binding. Binding modes and non-covalent interaction inventories are essential to design follow-up synthesis candidates. Two protocols are commonly applied to produce protein–ligand complexes: cocrystallization and soaking. Because of its time and cost effectiveness, soaking is the more popular method. Taking eight ligand hinge binders of protein kinase A, we demonstrate that cocrystallization is superior. Particularly for flexible proteins, such as kinases, and larger ligands cocrystallization captures more reliable the correct binding pose and induced protein adaptations. The geometrical discrepancies between soaking and cocrystallization appear smaller for fragment-sized ligands. For larger flexible ligands that trigger conformational changes of the protein, soaking can be misleading and underestimates the number of possible polar interactions due to inadequate, highly impaired positions of protein amino-acid side and main chain atoms. Thus, if applicable cocrystallization should be the gold standard to study protein–ligand complexes.     

钨中空位及其团簇的能量学和动力学性质参数

在总结前人钨中空位及其团簇的能量学和动力学行为的研究成果基础上，采用第一性原理方法系统计算了钨中空位及其团簇的结合能和扩散能垒。研究发现，交换关联泛函PW91和PBE较PBEsol、AM05和LDA更适合用于计算钨空位的能量学性质。基于第一性原理计算结果对文献中单空位形成能、双空位作用性质等争议性问题进行了讨论，并对钨经验势进行了评估。研究结果表明，钨中孤立单空位间总是相互排斥，而空位团簇（V_n>3）对单空位具有很强的吸引作用，其结合能随着所含空位个数增多呈现波动性增大的趋势。空位团簇稳定结构可通过最小化Wigner-Seitz表面积来确定，其结合能与V_n与V_n-1之间的Wigner-Seitz面积之差呈正比。     

不同热解工艺下半焦的微观结构特点及其对燃烧性能的影响

摘要：对比研究了3种直立内热炉半焦(熄焦方式分别为水泡熄焦、喷水熄焦及烟气干熄焦)及一种流化床热解半焦的微观结构及燃烧性能。通过对半焦组成、孔隙结构、有机官能团、碳化学结构及半焦微晶结构分析，获得了不同低温热解工艺半焦的组成及微观结构特点，明确了组成及微观结构与燃烧性能之间的关系。结果表明，不同热解工艺半焦的组成和微观结构差异明显，其对半焦的燃烧性能影响显著。干熄焦碳化学结构缺陷比例大，快速热解半焦孔隙结构发0达、挥发分高，与水喷焦相比水泡焦石墨化程度低；水喷焦燃烧性能优于水泡焦，干法所得半焦的燃烧性优于湿法；半焦的挥发分含量决定其燃点，在快升温速率条件下孔隙结构对半焦的燃烧性能影响较大，而慢升温速率条件下有序化度对半焦的燃烧性能影响较大。     

焦炉前反馈热工控制系统运行实践

焦炉生产是典型的大惯性、非线性、时变快的复杂系统，以“火落温度”为基础的焦炉前反馈热工控制系统，通过立火道温度自动测量与人工测温相关性分析、粗煤气温度测量与火落判断、标准温度的优化等运行实践，达到了自动火落时间判断、标准温度指导、加热和燃烧优化、高低温炉号判别等目的，对于稳定炉温、降低回炉煤气消耗、提高焦炭质量以及推进焦化企业技术进步具有重要意义。