Synthesis,Molecular Docking Analysis,and Biological Evaluations of Saccharide-Modified Sulfonamides as Carbonic Anhydrase IX Inhibitors

Based on the strategy of the “tail approach”, 15 novel saccharide-modified sulfonamides were designed and synthesised. The novel compounds were evaluated as inhibitors of three human carbonic anhydrase (CA) isoforms, namely cytoplasmic CA II, transmembrane CA IX, and XII. Most of these compounds showed good activity against CAs and high topological polar surface area (TPSA) values, which had a positive effect on the selective inhibition of transmembrane isoforms CA IX and XII. In the in vitro activity studies, compounds 16a, 16b, and 16e reduced the viability of HT-29 and MDA-MB-231 cells with a high expression of CA IX under hypoxia. The inhibitory activity of compound 16e on the human osteosarcoma cell line MG-63 with a high expression of CA IX and XII was better than that of AZM. Moreover, high concentrations of compounds 16a and 16b reversed the acidification of the tumour microenvironment. In addition, compound 16a had a certain inhibitory effect on the migration of MDA-MB-231 cells. All the above results indicate that the saccharide-modified sulfonamide has further research value for the development of CA IX inhibitors.     

A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening,Molecular Docking,and Molecular Dynamic Simulations

The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective pharmacological inhibition of CDK4/6 has proven to be beneficial in the treatment of estrogen receptor-positive (ER-positive) breast cancer, particularly improving the progression-free survival of patients. Thus, targeting specific inhibition on CDK4/6 is bound to increase therapeutic efficiency. This study aimed to obtain CDK4/6 inhibitors through a pharmacophore-based virtual screening of the ZINC15 purchasable compound database using the in silico method. The pharmacophore model was designed based on the FDA-approved cdk4/6 inhibitor structures, and molecular docking was performed to further screen the hit compounds obtained. A total of eight compounds were selected based on docking results and interactions with CDK4 and CDK6, using palbociclib as the reference drug. According to the results, the compounds of ZINC585292724 and ZINC585291674 were the best compounds based on free binding energy, as well as hydrogen bond stability, and, therefore, exhibit potential as starting points in the development of CDK4/6 inhibitors.     

分子动力学模拟的柔性对接

分子自动对接技术在过去二十年里取得很大发展和成功,但是仍然面对如何处理分子柔性这样一个难题。这篇综述概要介绍分子柔性对接技术的进展并重点介绍分子动力学模拟技术。     

微波交会对接雷达目标跟踪的卡尔曼滤波器设计

针对空间交会对接应用中追踪航天器对目标航天器的精密跟踪,采用三阶修正卡尔曼滤波器直接在球坐标系下对径向距离和径向速度进行联合跟踪,采用2个结构一致的二阶修正卡尔曼滤波器分别对俯仰角和俯仰角速度、方位角和方位角速度进行联合跟踪。提出一种状态噪声的实时估计算法,有效地解决了卡尔曼滤波应用中状态噪声的参数设计问题。仿真结果表明,本文设计的卡尔曼滤波器能够精确地跟踪目标航天器,同时具有较强的动态适应能力。     

交会对接微波雷达高精度测角算法

交会对接微波雷达需要完成100 km至20 m距离范围内、(±60°)×(±60°)宽视场范围内的角度测量,且测角精度要求在0.05°以内.针对兼具远近距离和宽视场测角需求,本文提出一种十形干涉仪几何对消测角算法.针对远距离测角精度无法满足精度要求的问题,采用基于当前统计模型的自适应Kalman滤波算法来提高测角精度....     

Thermus thermophilus木糖异构酶复合物模型的建立与分析

Thermus thermophilus木糖异构酶在高果糖浆的工业生产及木糖发酵重组菌的构建方面具有极其广阔的应用前景．本文主要运用结构分析和分子对接及计算软件,确定了Mg~2及木糖异构酶天然底物D-木糖在1BXB晶体结构中的定位,构建出1BXB复合物模型并进行评价与分析．通过对1BXB复合物模型1与1XIC的结构进行比较,发现所构建模型中D-木糖周围的残基在木糖异构酶中高度保守,并且D-木糖的定位与取向与1XIC中底物分子基本一致．     

航天器对接与捕获技术综述

航天器对接与捕获技术（Docking&capture technology,DCT）是实现航天器之间在轨连接、控制与分离,建立组合体间人员或资源交互的技术。对航天器对接与捕获技术的研究背景、发展历程、发展趋势、应用前景、技术内涵等内容进行了综述,首先从运载局限性催生对接技术发展、在轨服务需求爆发促进对接技术发展、空间碎片清理任务推动捕获技术发展等角度阐述了航天器对接与捕获技术的研究背景。从时间维度总结了该技术发展的三个历程,从技术途径角度概括了该技术的五个发展趋势。从在轨延寿、在轨手术、地外基建、轨道修正四个方面梳理了该技术的应用前景,提炼了该研究领域的八项关键技术。最后,给出了我国在该领域开展研究的方向和建议,为航天器在轨对接与捕获技术的未来研究提供参考。     

月球轨道交会对接微波雷达系统设计

针对月球轨道自主交会对接任务特点,设计一种测距、测速、测角、通信一体化的先进交会对接微波雷达系统。该雷达系统采用高速伪码延时测距、双程相干多普勒测速及相位干涉仪测角体制完成测量功能,采用QPSK调制与RS编码完成扩频通信功能,具有测量通信一体化、测量参数全、测量精度高、小型化低功耗、使用方便可靠等特点。经实际在轨验证,该雷达系统首次实现了月球轨道无人交会对接全程高精度多元信息测量及可靠双向通信,综合技术达到国际先进水平。     

Spectroscopic and Molecular Docking Investigation on the Interaction of Cumin Components with Plasma Protein: Assessment of the Comparative Interactions of Aldehyde and Alcohol with Human Serum Albumin

The interaction of the important plasma protein, human serum albumin (HSA), with two monoterpenes found in cumin oil, i.e., cuminaldehyde (4-isopropylbenzaldehyde) and cuminol (4-isopropylbenzyl alcohol), was studied in this paper. Both experimental and computational methods were utilized to understand the mechanism of binding. The UV absorption profile of HSA changes in the presence of both cuminaldehyde and cuminol, due to the interaction between HSA with both monoterpenes. The intrinsic fluorescence intensity of HSA was also quenched on the sequential addition of both ligands, due to change in the microenvironment of the fluorophore present in the former. Quenching of HSA by cuminaldehyde was much higher in comparison to that in the presence of cuminol. Fluorescence quenching data were analyzed using modified Stern-Volmer and Lineweaver-Burk methods, which suggested that the binding mechanism was of a static type for both ligands. In both cases, the binding was favored by the domination of hydrophobic as well as hydrogen bonding/Van der Waals forces. Both ligands partially unfolded the secondary structure of HSA, although the effect of cuminaldehyde was more pronounced, as compared to cuminol. The preferred binding site of cuminaldehyde and cuminol inside HSA was also the same; namely, drug binding site 1, located in subdomain IIA. The study showed that cuminaldehyde binds strongly with albumin as compared to its alcohol counterpart, which is due to the more hydrophobic nature of the former.     

Synthesis,Crystallographic, Quantum Chemical,Antitumor, and Molecular Docking/Dynamic Studies of 4-Hydroxycoumarin-Neurotransmitter Derivatives

In this contribution, four new compounds synthesized from 4-hydroxycoumarin and tyramine/octopamine/norepinephrine/3-methoxytyramine are characterized spectroscopically (IR and NMR), chromatographically (UHPLC-DAD), and structurally at the B3LYP/6-311++G*(d,p) level of theory. The crystal structure of the 4-hydroxycoumarin-octopamine derivative was solved and used as a starting geometry for structural optimization. Along with the previously obtained 4-hydroxycoumarin-dopamine derivative, the intramolecular interactions governing the stability of these compounds were quantified by NBO and QTAIM analyses. Condensed Fukui functions and the HOMO-LUMO gap were calculated and correlated with the number and position of OH groups in the structures. In vitro cytotoxicity experiments were performed to elucidate the possible antitumor activity of the tested substances. For this purpose, four cell lines were selected, namely human colon cancer (HCT-116), human adenocarcinoma (HeLa), human breast cancer (MDA-MB-231), and healthy human lung fibroblast (MRC-5) lines. A significant selectivity towards colorectal carcinoma cells was observed. Molecular docking and molecular dynamics studies with carbonic anhydrase, a prognostic factor in several cancers, complemented the experimental results. The calculated MD binding energies coincided well with the experimental activity, and indicated 4-hydroxycoumarin-dopamine and 4-hydroxycoumarin-3-methoxytyramine as the most active compounds. The ecotoxicology assessment proved that the obtained compounds have a low impact on the daphnia, fish, and green algae population.