Computer-aided design and discovery of protein–protein interaction inhibitors as agents for anti-HIV therapy

Protein–protein interactions (PPI) are involved in most of the essential processes that occur in organisms. In recent years, PPI have become the object of increasing attention in drug discovery, particularly for anti-HIV drugs. Although the use of combinations of existing drugs, termed highly active antiretroviral therapy (HAART), has revolutionized the treatment of HIV/AIDS, problems with these agents, such as the rapid emergence of drug-resistant HIV-1 mutants and serious adverse effects, have highlighted the need for further discovery of new drugs and new targets. Numerous investigations have shown that PPI play a key role in the virus’s life cycle and that blocking or modulating them has a significant therapeutic potential. Here we summarize the recent progress in computer-aided design of PPI inhibitors, mainly focusing on the selection of the drug targets (HIV enzymes and virus entry machinery) and the utilization of peptides and small molecules to prevent a variety of protein–protein interactions (viral–viral or viral–host) that play a vital role in the progression of HIV infection.     

Redesigning the DNA‐Targeted Chromophore in Platinum–Acridine Anticancer Agents: A Structure–Activity Relationship Study

Platinum–acridine hybrid agents show low‐nanomolar potency in chemoresistant non‐small cell lung cancer (NSCLC), but high systemic toxicity in vivo. To reduce the promiscuous genotoxicity of these agents and improve their pharmacological properties, a modular build–click–screen approach was used to evaluate a small library of twenty hybrid agents containing truncated and extended chromophores of varying basicities. Selected derivatives were resynthesized and tested in five NSCLC cell lines representing large cell, squamous cell, and adenocarcinomas. 7‐Aminobenz[c]acridine was identified as a promising scaffold in a hybrid agent ( P1–B1 ) that maintained submicromolar activity in several of the DNA‐repair proficient and p53‐mutant cancer models, while showing improved tolerability in mice by 32‐fold compared to the parent platinum–acridine ( P1–A1 ). The distribution and DNA/RNA adduct levels produced by the acridine‐ and benz[c]acridine‐based analogues in NCI‐H460 cells (confocal microscopy, ICP‐MS), and their ability to bind G‐quadruplex forming DNA sequences (CD spectroscopy, HR‐ESMS) were studied. P1–B1 emerges as a less genotoxic, more tolerable, and potentially more target‐selective hybrid agent than P1–A1 .     

Probing the Anticancer Mechanism of (−)‐Ainsliatrimer A through Diverted Total Synthesis and Bioorthogonal Ligation

Herein, we report an efficient approach for exploring the novel anticancer mechanism of (?)‐ainsliatrimer A, a structurally complex and unique trimeric sesquiterpenoid, through a combined strategy of diverted total synthesis (DTS) and bioorthogonal ligation (TQ ligation), which allowed us to visualize the subcellular localization of this natural product in live cells. Further biochemical studies facilitated by pretarget imaging revealed that PPARγ, a nucleus receptor, was a functional cellular target of ainsliatrimer A. We also confirmed that the anticancer activity of ainsliatrimer A was caused by the activation of PPARγ.     

Enhanced Propene/Propane Separation by Directional Decoration of the 12‐Membered Rings of Mordenite with ZIF Fragments

Propene/propane separation is challenging due to the very small difference in molecular sizes, boiling points and condensabilities between these molecules. Herein, we report a strategy of introducing ZIF fragments into traditional mordenite (MOR) zeolite to decorate the 12‐membered ring of MOR. After decoration, the originally ineffective zeolite MOR exhibited high kinetic propene/propane selectivities (139 at 25 °C) and achieved efficient propene/propane separation. The propene/propane separation potentials of the resulting adsorbents were further confirmed by breakthrough experiments with equimolar propene/propane (50/50) mixtures.     

Inverse screening of Simvastatin kinase targets from glioblastoma druggable kinome

The statin drug Simvastatin is a HMG-CoA reductase inhibitor that has been widely used to lower blood lipid. However, the drug is clinically observed to reposition a significant suppressing potency on glioblastoma (GBM) by unexpectedly targeting diverse kinase pathways involved in GBM tumorigensis. Here, an inverse screening strategy is described to discover potential kinase targets of Simvastatin. Various human protein kinases implicated in GBM are enriched to define a druggable kinome; the binding behavior of Simvastatin to the kinome is profiled systematically via an integrative computational approach, from which most kinases have only low or moderate binding potency to Simvastatin, while only few are identified as promising kinase hits. It is revealed that Simvastatin can potentially interact with certain known targets or key regulators of GBM such as ErbB, c-Src and FGFR signaling pathways, but exhibit low affinity to the well-established GBM target of PI3K/Akt/mTOR pathway. Further assays determine that Simvastatin can inhibit kinase hits EGFR, MET, SRC and HER2 at nanomolar level, which are comparable with those of cognate kinase inhibitors. Structural analyses reveal that the sophisticated T790 M gatekeeper mutation can considerably reduce Simvastatin sensitivity to EGFR by inducing the ligand change between different binding modes.     

In vitro antiproliferative activity of glabridin derivatives and their in silico target identification

Abstract

Novel Mannich base derivatives of glabridin were synthesized and their antiproliferative activity were performed along with our previously reported glabridin-chalcone hybrids molecules (GCHMs) against various human cell lines MDA-MB-231 (breast adenocarcinoma), HEK-293 (embryonic kidney cell line), K562 (leukemia), MCF-7 (breast adenocarcinoma), HeLa (cervix adenocarcinoma), HepG2 (hepatocellular carcinoma) and WRL-68 (hepatic carcinoma). The result showed that the glabridin significantly reduced cell proliferation with IC₅₀ ranges from 3.67 to 58.30?µM against all the tested cell lines. The remarkable reduction in antiproliferative activity 2’,4’-dimethoxyglabridin and GCHMs compounds with phenolic OH groups protected by methoxy (OCH₃) groups suggested that the free OH groups are essential factor for the antiproliferative activity of glabridin and its derivatives. The Mannich base derivatives of glabridin showed moderate activity IC₅₀ (2.20–>95.78?µM). Furthermore, in silico target identification analysis revealed that AKT1, DECR1 and NOS1 are the potential targets for glabridin and their derivatives.     

中高分辨力遥感图像中飞机目标自动识别算法研究

提出了一种中高分辨力的航空航天遥感图像中飞机目标快速自动识别的新算法。在分割和分类过程中充分利用飞机目标的先验知识,提出了一种改进区域分割方法,并应用树分类器对飞机目标进行自动识别。所提出的改进区域分割方法较好地实现了区域分割中阈值的准确自动选取,克服了复杂背景图像中小目标的全局阈值自动分割的失效问题。采用二叉树分类器,通过提取简单的目标几何特征,分层进行种类识别,提高了识别速度,降低了漏检率和虚警率。运用该方法进行了实验。结果表明,识别率达到了100%。     

基于DIGNET网络的数据融合方法

针对数据融合和目标识别的特点,提出了基于DIGNET自组织聚类人工神经网络的数据融合方法。考虑到多传感器系统测量多个参量的特点,用并行的子网络结构代替中间隐层,实现了基于决策层的信息融合目标识别。利用仿真数据对基于DIGNET的数据融合方法进行了实验研究。实验结果表明,该方法具有数据正确分类率高和抗噪能力强等优点,有效地实现了融合识别。将该方法应用于前视红外和可见光双传感器目标跟踪系统的数据融合识别是可行的。     

基于红外/毫米波双模融合的目标识别方法

在数据融合的基础上,以红外/毫米波双模传感器的智能融合结构为模型,将模糊神经网络与D-S证据理论相结合,提出了一种新的目标识别方法.该算法根据红外/毫米波传感器的性能及工作范围,构造模糊变量作为神经网络的输入,根据神经网络的不同输出判别目标的真伪,并利用D-S证据理论进行目标身份识别.仿真结果证明了该算法的可行性.     

不同材料弹体超声速侵彻钢筋混凝土靶的结构破坏对比实验

设计了超声速钻地结构弹,采用203 mm口径的火炮,开展了25 kg量级弹体在1100~1300 m/s速度范围内侵彻钢筋混凝土靶的实验研究,应用数值仿真对弹体侵彻钢筋混凝土靶的过程进行了模拟计算。基于实验和仿真结果,对超声速侵彻条件下两种金属材料弹体的结构响应、质量损失等问题进行了分析。结果表明:在超声速侵彻钢筋混凝土靶的过程中,两种金属材料的弹体结构变形破坏形式主要为头部侵蚀和侧壁磨蚀,头部侵蚀量的大小与弹体壳体材料有关,高强度G50钢材料更适合用于1200 m/s速度量级的超声速侵彻环境。对出现的“径缩”现象作了初步分析,并对今后工程应用的结构弹体设计提出了指导意见。