Recent Advances in Discovery of Lead Structures from Microbial Natural Products: Genomics- and Metabolomics-Guided Acceleration

Natural products (NPs) are evolutionarily optimized as drug-like molecules and remain the most consistently successful source of drugs and drug leads. They offer major opportunities for finding novel lead structures that are active against a broad spectrum of assay targets, particularly those from secondary metabolites of microbial origin. Due to traditional discovery approaches’ limitations relying on untargeted screening methods, there is a growing trend to employ unconventional secondary metabolomics techniques. Aided by the more in-depth understanding of different biosynthetic pathways and the technological advancement in analytical instrumentation, the development of new methodologies provides an alternative that can accelerate discoveries of new lead-structures of natural origin. This present mini-review briefly discusses selected examples regarding advancements in bioinformatics and genomics (focusing on genome mining and metagenomics approaches), as well as bioanalytics (mass-spectrometry) towards the microbial NPs-based drug discovery and development. The selected recent discoveries from 2015 to 2020 are featured herein.     

Friedel-Crafts:伟大的反应与伟大的合作者*

傅克反应(Friedel-Crafts Reaction)是迄今为止最古老、应用最长久的碳-碳键形成反应之一,广泛应用于医药、染料、石油等化学工业的各个分支。自1877年被发现以来,傅克反应已经发展成为最经典的有机反应之一,被写进现代有机化学教科书。跟其他重大化学发现类似,傅克反应的发现过程也充满着惊喜和意外,折射出化学家敏锐的洞察力和非同寻常的逻辑推理能力。本文通过整理一些早期的国内外文献和相关化学史料,简述了傅克反应发现的历史背景、发现过程,回顾了两位化学家查理斯·傅列德尔(Charles Friedel)和杰姆斯·克拉夫茨(James Crafts)的一些重要成长经历以及他们接近40年的伟大合作历程。     

低能C36团簇在金刚石(100)晶面沉积时的影响因素

"使用Brenner-LJ拟合势描述了金刚石与C36团簇原子间的相互作用,并用分子动力学模拟的方法研究单个C36(D6h)在金刚石(100)晶面的沉积机制．通过仿真实验分析了C36团簇的入射能量、入射点位置、入射姿势、入射角度等因素对其成核初期化学吸附过程以及沉积后其稳定性的影响．研究发现：由于C36入射点位置及入射姿势的不同,其在金刚石(100)晶面沉积时的沉积阈值最小值为20 eV,最大值为60 eV;在入射角不超过60o斜射时,由于水平运动分量的存在,C36可能翻滚及平滑至成键能量较小的区域后再成键     

Guided Antitumoural Drugs: (Imidazol-2-ylidene)(L)gold(I) Complexes Seeking Cellular Targets Controlled by the Nature of Ligand L

Three [1,3-diethyl-4-(p-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)imidazol-2-ylidene](L)gold(I) complexes, 4 a (L=Cl), 5 a (L=PPh₃), and 6 a (L=same N-heterocyclic carbene (NHC)), and their fluorescent [4-(anthracen-9-yl)-1,3-diethyl-5-phenylimidazol-2-ylidene](L)gold(I) analogues, 4 b , 5 b , and 6 b , respectively, were studied for their localisation and effects in cancer cells. Despite their identical NHC ligands, the last three accumulated in different compartments of melanoma cells, namely, the nucleus ( 4 b ), mitochondria ( 5 b ), or lysosomes ( 6 b ). Ligand L was also more decisive for the site of accumulation than the NHC ligand because the couples 4 a / 4 b , 5 a / 5 b , and 6 a / 6 b , carrying different NHC ligands, afforded similar results in cytotoxicity tests, and tests on targets typically found at their sites of accumulation, such as DNA in nuclei, reactive oxygen species and thioredoxin reductase in mitochondria, and lysosomal membranes. Regardless of the site of accumulation, cancer cell apoptosis was eventually induced. The concept of guiding a bioactive complex fragment to a particular subcellular target by secondary ligand L could reduce unwanted side effects.     

基于语义的软件服务故障自动诊断模型

模仿学习是机器人仿生机制研究的主要内容之一,即通过观察、理解、学习、模仿示教行为实现机器人的仿生特性。基于高斯过程分别表达采集离散示教信号所构成的示教轨迹和含有未知参数策略的模仿轨迹,构建模仿学习方法框架,将概率模型匹配引入到模仿学习中,以KL散度为代价函数比较两种轨迹的概率分布,运用梯度下降法寻求使KL散度最小的最优模仿控制策略,将策略应用于模仿机器人以完成与示教相同的模仿任务。以关节型机器人的机械臂摆动行为模仿为学习任务进行仿真,结果表明基于概率轨迹匹配的模仿学习方法能够实现机械臂摆动行为模仿,学习过程较传统方法简易且学习效果较好。     

铯47D精细能级超冷里德堡原子自由演化的动力学研究

用连续窄线宽激光器将超冷铯里德堡原子分别激发到47D_3/2, 47D_5/2精细态, 观察了处于里德堡精细态的铯原子向超冷铯等离子体自由演化的过程, 详细对比了不同精细态的铯里德堡原子预电离时间、电离速率以及等离子体的转化效率. 将里德堡原子快速转化为等离子体的过程解释为局域势阱内由预电离产生的电子与里德堡原子的快速碰撞导致的雪崩电离.     

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.