Comparison of Structure‐ and Ligand‐Based Virtual Screening Protocols Considering Hit List Complementarity and Enrichment Factors

Structure‐ and ligand‐based virtual‐screening methods (docking, 2D‐ and 3D‐similarity searching) were analysed for their effectiveness in virtual screening against four different targets: angiotensin‐converting enzyme (ACE), cyclooxygenase 2 (COX‐2), thrombin and human immunodeficiency virus 1 (HIV‐1) protease. The relative performance of the tools was compared by examining their ability to recognise known active compounds from a set of actives and nonactives. Furthermore, we investigated whether the application of different virtual‐screening methods in parallel provides complementary or redundant hit lists. Docking was performed with GOLD, Glide, FlexX and Surflex. The obtained docking poses were rescored by using nine different scoring functions in addition to the scoring functions implemented as objective functions in the docking algorithms. Ligand‐based virtual screening was done with ROCS (3D‐similarity searching), Feature Trees and Scitegic Functional Fingerprints (2D‐similarity searching). The results show that structure‐ and ligand‐based virtual‐screening methods provide comparable enrichments in detecting active compounds. Interestingly, the hit lists that are obtained from different virtual‐screening methods are generally highly complementary. These results suggest that a parallel application of different structure‐ and ligand‐based virtual‐screening methods increases the chance of identifying more (and more diverse) active compounds from a virtual‐screening campaign.     

基于星间测量的航天器精密定轨技术研究

在我国自主实施的交会对接任务中,2个空间目标进行了数次对接试验,在近距离导引段使用星间测量数据进行自主导引。针对2个航天器对接过程中的星间测量数据建立观测模型,并设计了多目标定轨的算法,将单目标的绝对测量融合到两目标联合定轨的技术中,实现了对空间多个目标的精确定轨。最终分析表明,星间测量数据优于地面测量精度,多目标定轨达到了地面精确测控的水平,同时避免了由于多目标同时跟踪而导致的地面测控资源分配的问题,为后续载人航天任务的测控模式提供了借鉴。     

浅谈模具设计与制造专业教学与生产过程中的对接

依据高职教育工学结合思想,模具设计与制造专业教师通过深度的教育观念转变、高标准的顶岗锻炼,在严格的考核制度和资金大力支持下,成功实现了教学过程与生产过程对接。     

Comparative analysis of polyspecificity of the endogenous tRNA synthetase of different expression host towards photocrosslinking amino acids using an in silico approach

Photo-induced covalent crosslinking has emerged as the powerful strategy for analyzing and characterizing the protein–protein interaction and mapping protein 3D conformations. In the last decades, a number of photocrosslinking amino acids have been reported but only a few have been efficiently utilized for photocrosslinking purposes. Recently, incorporation of diazirine containing photoactivatable analogs such as photo-methionine, photo-leucine, photo-isoleucine and photo-lysine into target proteins were accomplished in live cells (Human A549cells, HEK 293) by depleting corresponding natural amino acid and supplementing these analogs in the medium. Likewise, incorporation of photo-methionine and photo-leucine is also reported in E. coli. Incorporation of these unnatural amino acids were demonstrated only in a limited number species, thereby conventional methods have been utilized for the protein–protein interaction study in other species. With this in mind, we studied in silico analysis of polyspecificity of four endogenous tRNA synthetases (LeuRS, IleRS, MetRS, and LysRS) from six different species such as Escherichia coli, Pseudomonas fluorescens, Corynebacterium glutamicum, Saccharomyces cerevisiae, Aspergillus oryzae and Homo sapiens towards its photocrosslinking amino acids. In addition, here we describe the active site similarity of different protein bio-factories. Based on the active site similarity and similar binding mode, we predicted that the endogenous tRNA synthetases of all the species are reactive to corresponding photoactivatable analogs. This is the first in silico study to demonstrate that the photocrosslinking unnatural amino acids are recognized by the endogenous tRNA synthetases of different protein expression biofactories.     

Structure-guided cancer blockade between bioactive bursehernin and proteins: Molecular docking and molecular dynamics study

Bursehernin (5′-desmethoxyyatein) is a natural lignan, which has anti-tumor activity in vitro. In this study, the binding-inhibitory effects of bursehernin were screening on selected 80 proteins associated with cancer pathway. The computational analysis suggested inhibitory effect due to bursehernin towards proteins related to cancer proliferation, including FMS kinase receptor, heat shock protein 90-α (Hsp90-α), adenylate cyclase 10 (ADCY10), mitogen-activated protein kinase kinase (MEK1), and α-tubulin. Moreover, bursehernin could interfere with cell cycle progression via binding to cyclin B proteins. Among all screened proteins, the compound showed an interesting binding affinity to the FMS kinase receptor. The binding mode studies by molecular dynamic technique showed that aromatic ring of bursehernin compound was responsible for compound-protein interaction through pi-pi stacking with Tyr105 and Phe178 of the FMS kinase receptor. This study suggests that bursehernin has potential for development as an anti-tumor agent with an anti-proliferation, and cell cycle arrest inducing, although further studies are needed.     

An analysis of conformational changes on proteinprotein association: implications for predictive docking

Conformational changes on complex formation have been measuredfor 39 pairs of structures of complexed proteins and unboundequivalents, averaged over interface and non-interface regionsand for individual residues. We evaluate their significanceby comparison with the differences seen in 12 pairs of independentlysolved structures of identical proteins, and find that justover half have some substantial overall movement. Movementsinvolve main chains as well as side chains, and large changesin the interface are closely involved with complex formation,while those of exposed non-interface residues are caused byflexibility and disorder. Interface movements in enzymes aresimilar in extent to those of inhibitors. All eight of the complexes(six enzyme–inhibitor and two antibody–antigen) thathave structures of both components in an unbound form availableshow some significant interface movement. However, predictivedocking is successful even when some of the largest changesoccur. We note however that the situation may be different insystems other than the enzyme–inhibitors which dominatethis study. Thus the general model is induced fit but, becausethere is only limited conformational change in many systems,recognition can be treated as lock and key to a first approximation.     

基于运载火箭加泄连接器自动对接系统的控制流程研究

针对运载火箭加注时连接器与加注活门的自动对接系统控制流程展开研究,提出将机械结构按照耦合程度分类的方法,将控制流程的设计从具体的机械结构中脱离出来,加强控制流程设计的通用性。通过仿真分析证明控制流程存在的必要性,给出了自动对接系统的控制流程,并依据此流程进行仿真分析,结果表明,控制流程可满足自动对接系统要求。     

基于直接升力的空中加油对接飞行控制

为解决传统空中加油对接过程中受油机纵向轨迹跟踪控制存在时间滞后的问题,提出一种基于直接升力的空中加油对接飞行控制方法.采用非线性L1制导的方法生成横纵向加速度指令,设计2种直接升力方案对受油机纵向轨迹控制加以改进,采用动态逆方法对姿态回路设计,通过扩张状态观测器对动态逆内回路进行补偿.仿真结果表明:采用的2种方案均能消除纵向轨迹跟踪的时间滞后,实现受油机纵向轨迹的快速响应,完成空中加油的成功对接.     

The Discovery of Potentially Selective Human Neuronal Nitric Oxide Synthase (nNOS) Inhibitors: A Combination of Pharmacophore Modelling,CoMFA, Virtual Screening and Molecular Docking Studies

Neuronal nitric oxide synthase (nNOS) plays an important role in neurotransmission and smooth muscle relaxation. Selective inhibition of nNOS over its other isozymes is highly desirable for the treatment of neurodegenerative diseases to avoid undesirable effects. In this study, we present a workflow for the identification and prioritization of compounds as potentially selective human nNOS inhibitors. Three-dimensional pharmacophore models were constructed based on a set of known nNOS inhibitors. The pharmacophore models were evaluated by Pareto surface and CoMFA (Comparative Molecular Field Analysis) analyses. The best pharmacophore model, which included 7 pharmacophore features, was used as a search query in the SPECS database (SPECS^®, Delft, The Netherlands). The hit compounds were further filtered by scoring and docking. Ten hits were identified as potential selective nNOS inhibitors.     

Biochemical Characterization of a Carboxylesterase from the Archaeon Pyrobaculum sp. 1860 and a Rational Explanation of Its Substrate Specificity and Thermostability

In this work, genome mining was used to identify esterase/lipase genes in the archaeon Pyrobaculum sp. 1860. A gene was cloned and functionally expressed in Escherichia coli as His-tagged protein. The recombinant enzyme (rP186_1588) was verified by western blotting and peptide mass fingerprinting. Biochemical characterization revealed that rP186_1588 exhibited optimum activity at pH 9.0 and 80 °C towards p-nitrophenyl acetate (K_m: 0.35 mM, k_cat: 11.65 s⁻¹). Interestingly, the purified rP186_1588 exhibited high thermostability retaining 70% relative activity after incubation at 90 °C for 6 h. Circular dichroism results indicated that rP186_1588 showed slight structure alteration from 60 to 90 °C. Structural modeling showed P186_1588 possessed a typical α/β hydrolase’s fold with the catalytic triad consisting of Ser₉₇, Asp₁₄₇ and His₁₇₂, and was further confirmed by site-directed mutagenesis. Comparative molecular simulations at different temperatures (300, 353, 373 and 473 K) revealed that its thermostability was associated with its conformational rigidity. The binding free energy analysis by MM-PBSA method revealed that the van der Waals interaction played a major role in p-NP ester binding for P186_1588. Our data provide insights into the molecular structures of this archaeal esterase, and may help to its further protein engineering for industrial applications.