酶-配体复合物亲和性的计算

描述了一种新的计算酶－配体复合物亲和性的方法．它考虑了酶－配体结合过程中自由能变化的各主要因素，并利用经验公式加以计算、从蛋白质结构数据库中选取了66个酶－配体复合物作为训练集，利用回归分析得出最后的模型．此模型通用于各种类型的酶－配体复合物，计算结果比技准确，预测算合物解离常数的平均偏差小于一个数量级．此方法还可以定量评价配体分子中每个部分对结合过程的贡献大小，可以为先导他合物的优化提供非常直接的信息     

生物无机化学基本反应之一——生物大分子配体参与的配体间竞争金属离子的反应

生物大分子参与的大小分子配体间竞争金属离子的反应是生物无机化学的基本反应之—。由于生物大分子具有多结合部位、柔性及金属离子往往深藏于生物大分子的疏水环境中等特点,使得这类反应与简单的小分子配体间竞争金属离子的反应有所不同。本文对这类反应的热力学、动力学、反应机理及影响因素进行了讨论。     

药物配体与生物大分子受体相互作用核磁共振的研究进展

药物与生物体内目标大分子之间的相互作用,是决定药物药理活性和代谢稳定性的主要因素。如何快速高效地识别出能与靶分子相互作用且能抑制其体外活性的药物分子,是制药工业普遍关注的问题。核磁共振已经成为研究小分子配体和生物大分子相互作用的一种非常重要的手段。检测小分子配体信号在作用过程中的变化以识别药物分子,是核磁共振进行药物筛选的主要方法之一。本文介绍了近年来这方面的研究进展。     

新型膦胺配体羰基钌化合物的合成及其催化性能研究

以十二羰基三钌和o-PPh2C6H4NR2(R=H,Me)配体为原料,成功制备了三种新型羰基钌化合物(μ-o-PPh2-C6H4NH)Ru3(μ-H)(CO)9(2)、(o-PPh2C6H4NH)2Ru(CO)2(3)和(μ-o-PPh2C6H4NMe2)2Ru(CO)3(4).对这三个化合物进行了核磁共振和红外谱学、元素分析和X射线单晶衍射分析表征,并对这三个化合物进行了催化性能研究.化合物2和4可催化苯甲醛加氢反应生成苯甲醇,但是3没有催化活性.从实验角度阐述了膦胺配体钌催化剂的结构与性能关联,进一步探讨了加氢催化反应失活的可能原因.     

IPET:测定独个生物大分子三维空间结构的实验方法

蛋白质的动态特性和结构活性对于蛋白质功能的调控具有根本意义。传统的结构确定方法(包括X射线和电子显微镜单颗粒分析技术等)往往需要成千上万不同蛋白质分子的平均信号,因此难以确定蛋白质分子的动态结构。而电子显微断层成像技术是一种对独个生物个体结构从不同的观测角度照相、并计算来恢复该个体的三维结构密度图的方法。传统的冷冻电子断层成像重构方法采用整个大尺寸电镜图像进行重构计算,通常用来研究细菌、细胞切片等大尺寸生物个体在较低分辨率下的结构;由于分辨率的限制,不足以获得小尺寸的蛋白质分子的结构细节。最近,任罡研究小组提出一种独个生物颗粒的电子显微断层成像方法(individual-particle electron tomography,IPET)。该方法通过减小图像尺寸(直至所选区域只包含单个蛋白质分子)的策略,运用提出的FETR(focused electron tomography reconstruction)算法来提高独个大分子重构的分辨率。此方法不需要初始模型和大量分子的平均信号,同时能够容忍一定的测角误差。本文综述了IPET/FETR方法在确定独个分子结构过程中的具体步骤以及如何应用该方法来研究蛋白动态特性和结构变化特征。期望通过该综述和国内同行交流,分享最新的前沿研究,为赶超世界科技前沿的建设添砖加瓦。     

无配体钯催化的烯丙基酯离去基团保留的高选择性芳基化反应

带有易离去基团的烯丙基酯类化合物的Heck反应由于竞争反应和选择性的难以控制，使得该反应一直属于比较挑战性的领域：（1）烯丙基酯类化合物很容易经过C-O键断裂和零价钯发生氧化加成（patha），与芳基卤化物对零价钯的氧化加成反应（pathb）形成竞争；（2）在钯物种对双键进行插入反应后，     

水分子对磺酰脲类分子构效关系影响的研究

磺酰脲超高效除草剂是进入到植物体内抑制 ALS酶而起作用的 .其结构通式见 Scheme1 .　　人们发现 ,在基本结构不变的前提下 ,Li 为 N或 C原子 ,R2 ,R4等的取代基不同将导致除草活性的差异 .而药物分子的构象与其生物活性密切相关 .大多数药物分子进入到植物体内后是在水相体系中与受体结合的 .探讨构效关系时 ,必须考虑水分子对药物分子构象的影响 [1] .本文首次报道在磺酰脲类分子中的有关研究 .1　研究对象及计算方法和过程1 .1　研究对象　对合成并进行生物测定的 35个磺酰脲类化合物 [2 ] 进行研究 ,其活性范围比较宽 ,p I5 0值 (…     

高聚物溶液中大分子链尺寸的研究(Ⅲ)——一种测算高分子溶液第二维里系数的新方法

将高聚物溶液中大分子链尺寸对浓度的依赖关系与Zimm稀溶液第二维里系数的统计力学硬球模型相结合,借助聚合物的特性粘数、Mark-Houwink方程或分子量,计算聚合物-溶剂体系在稀溶液浓度范围内π/C或H·C/τ的模拟实验值.再以π/C或H·C/τ与浓度线型回归中的始斜率求体系的第二维里系数A₂,计算了30种聚合物-溶剂体系的295个不同分子量的A₂值,结果均与其实验值吻合较好,且明显优于其它理论模型测算的结果.     

高聚物溶液中大分子链尺寸的研究——高分子溶液渗透压的计算

本文根据前文提出的高聚物溶液中大分子链尺寸的浓度依赖关系式,结合Zimm用于计算稀溶液第二维里系数的统计力学硬球模型,利用聚合物的数均分子量及其Mark-Houwink方程,计算了16种聚合物-溶剂体系在不同溶液浓度范围内的比浓渗透压。结果表明,计算值与稀溶液、亚浓溶液浓度范围内的实验值相当一致,甚至与浓溶液浓度范围内的实验值也十分接近。这显示了本法用于计算高分子溶液的渗透压是令人满意的。     

Structure-Activity Relationship of NF023 Derivatives Binding to XIAP-BIR1

Inhibitors of Apoptosis Proteins (IAPs) are conserved E3-ligases that ubiquitylate substrates to prevent apoptosis and activate the NF-kB survival pathway, often deregulated in cancer. IAPs-mediated regulation of NF-kB signaling is based on the formation of protein complexes by their type-I BIR domains. The XIAP-BIR1 domain dimerizes to bind two TAB1 monomers, leading to downstream NF-kB activation. Thus, impairment of XIAP-BIR1 dimerization could represent a novel strategy to hamper cell survival in cancer. To this aim, we previously reported NF023 as a potential inhibitor of XIAP-BIR1 dimerization. Here we present a thorough analysis of NF023 binding to XIAP-BIR1 through biochemical, biophysical and structural data. The results obtained indicate that XIAP-BIR1 dimerization interface is involved in NF023 binding, and that NF023 overall symmetry and the chemical features of its central moiety are essential for an efficient interaction with the protein. Such strategy provides original hints for the development of novel BIR1-specific compounds as pro-apoptotic agents.     

Rational Design and Asymmetric Synthesis of Potent and Neurotrophic Ligands for FK506‐Binding Proteins (FKBPs)

To create highly efficient inhibitors for FK506‐binding proteins, a new asymmetric synthesis for pro‐(S)‐C⁵‐branched [4.3.1] aza‐amide bicycles was developed. The key step of the synthesis is an HF‐driven N‐acyliminium cyclization. Functionalization of the C⁵ moiety resulted in novel protein contacts with the psychiatric risk factor FKBP51, which led to a more than 280‐fold enhancement in affinity. The most potent ligands facilitated the differentiation of N2a neuroblastoma cells with low nanomolar potency.     

Fluorinated Carbohydrates as Lectin Ligands: Versatile Sensors in 19F‐Detected Saturation Transfer Difference NMR Spectroscopy

As a novel approach for studying carbohydrate–lectin interactions spectroscopically, we combine the resolution and specificity of ¹⁹F‐detected NMR spectroscopy with the sensitivity of the saturation transfer difference (STD) technique. The resulting background‐free ¹⁹F‐STD spectra open a promising perspective for broad application with medical relevance, for example, in drug discovery.

     

Stalis: A Computational Method for Template-Based Ab Initio Ligand Design

Proteins interact with small molecules through specific molecular recognition, which is central to essential biological functions in living systems. Therefore, understanding such interactions is crucial for basic sciences and drug discovery. Here, we present S tructure t emplate-based a b initio li gand design s olution (Stalis), a knowledge-based approach that uses structure templates from the Protein Data Bank libraries of whole ligands and their fragments and generates a set of molecules (virtual ligands) whose structures represent the pocket shape and chemical features of a given target binding site. Our benchmark performance evaluation shows that ligand structure-based virtual screening using virtual ligands from Stalis outperforms a receptor structure-based virtual screening using AutoDock Vina, demonstrating reliable overall screening performance applicable to computational high-throughput screening. However, virtual ligands from Stalis are worse in recognizing active compounds at the small fraction of a rank-ordered list of screened library compounds than crystal ligands, due to the low resolution of the virtual ligand structures. In conclusion, Stalis can facilitate drug discovery research by designing virtual ligands that can be used for fast ligand structure-based virtual screening. Moreover, Stalis provides actual three-dimensional ligand structures that likely bind to a target protein, enabling to gain structural insight into potential ligands. Stalis can be an efficient computational platform for high-throughput ligand design for fundamental biological study and drug discovery research at the proteomic level. © 2019 Wiley Periodicals, Inc.     

A Photoaffinity-Based Fragment-Screening Platform for Efficient Identification of Protein Ligands

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space. Presented here is a fragment-screening platform, termed PhABits (PhotoAffinity Bits), which utilizes a library of photoreactive fragments to covalently capture fragment–protein interactions. Hits can be profiled to determine potency and the site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. The PhABit platform is envisioned to be widely applicable to novel protein targets, identifying starting points in the development of therapeutics.     

A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics

The vascular endothelial growth factor (VEGF) family of cytokines plays a key role in vasculogenesis, angiogenesis, and lymphangiogenesis. VEGF-A is the main member of this family, alongside placental growth factor (PlGF), VEGF-B/C/D in mammals, and VEGF-E/F in other organisms. To study the activities of these growth factors under physiological and pathological conditions, resulting in therapeutic applications in cancer and age-related macular degeneration, blocking ligands have been developed. These have mostly been large biomolecules like antibodies. Ligands with high affinities, at least in the nanomolar range, and accurate structural data from X-ray crystallography and NMR spectroscopy have been described. They constitute the main focus of this overview, which evidences similarities and differences in their binding modes. For VEGF-A ligands, and to a limited extent also for PlGF, a transition is now observed towards developing smaller ligands like nanobodies and peptides. These include unnatural amino acids and chemical modifications for designed and improved properties, such as serum stability and greater affinity. However, this review also highlights the scarcity of such small molecular entities and the striking lack of small organic molecule ligands. It also shows the gap between the rather large array of ligands targeting VEGF-A and the general absence of ligands binding other VEGF members, besides some antibodies. Future developments in these directions are expected in the upcoming years, and the study of these growth factors and their promising therapeutic applications will be welcomed.     

Drug Repurposing for COVID-19: A Review and a Novel Strategy to Identify New Targets and Potential Drug Candidates

In December 2019, the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19) was first identified in the province of Wuhan, China. Since then, there have been over 400 million confirmed cases and 5.8 million deaths by COVID-19 reported worldwide. The urgent need for therapies against SARS-CoV-2 led researchers to use drug repurposing approaches. This strategy allows the reduction in risks, time, and costs associated with drug development. In many cases, a repurposed drug can enter directly to preclinical testing and clinical trials, thus accelerating the whole drug discovery process. In this work, we will give a general overview of the main developments in COVID-19 treatment, focusing on the contribution of the drug repurposing paradigm to find effective drugs against this disease. Finally, we will present our findings using a new drug repurposing strategy that identified 11 compounds that may be potentially effective against COVID-19. To our knowledge, seven of these drugs have never been tested against SARS-CoV-2 and are potential candidates for in vitro and in vivo studies to evaluate their effectiveness in COVID-19 treatment.