载脂蛋白A-Ⅰ(apolipoprotein A-Ⅰ,ApoA-Ⅰ)是高密度脂蛋白(high density lipoprotein,HDL)的主要蛋白成分,在胆固醇逆转运(reverse cholesterol transport,RCT)中发挥关键作用,是抗动脉粥样硬化(atherosclerosis,As)药物研发的重要靶标.靶向ApoA-Ⅰ α螺旋研发的模拟肽和基于重组ApoA-Ⅰ研发的HDL模拟肽已进入临床试验,展示了良好的促RCT与抗As活性.本文综述了ApoA-Ⅰ的结构和功能,ApoA-Ⅰ与ABCA1(ATP-binding cassette transporter A1)、LCAT(lecithin cholesterol acyl transferase)、SR-B1(scavenger receptor class B type 1)的分子互作机制,总结了靶向ApoA-Ⅰ模拟肽的研究进展,以期为模拟肽类抗As新药研发提供参考.

KW-2478 is a promising anti-cancer lead compound targeting to the molecular chaperone heat shock protein 90 N (Hsp90N). Absence of complex crystal structure of Hsp90N-KW-2478, however, hampered further structure optimization of KW-2478 and understanding on the molecular interaction mechanism. Herein, a high-resolution complex crystal structure of Hsp90N-KW-2478 was determined by X-ray diffraction (XRD, resolution limit: 1.59 Å; PDB ID: 6LT8) and their molecular interaction was analyzed in detail, which suggested that KW-2478 perfectly bound in the N-terminal ATP-binding pocket of Hsp90 to disable its molecular chaperone function, therefore suppressed or killed cancer cells. The results from thermal shift assay (TSA, ΔTm, 18.82 ± 0.51 °C) and isothermal titration calorimetry (ITC, Kd, 7.30 ± 2.20 nM) suggested that there is an intense binding force and favorable thermodynamic changes during the process of KW-2478 binding with Hsp90N. Additionally, KW-2478 exhibited favorable anti-NSCLC activity in vitro, as it inhibited cell proliferation (IC50, 8.16 μM for A549; 14.29 μM for H1975) and migration, induced cell cycle arrest and promoted apoptosis. Thirty-six novel KW-2478 derivatives were designed, based on the complex crystal structure and molecular interaction analysis of Hsp90N-KW-2478 complex. Among them, twenty-two derivatives exhibited increased binding force with Hsp90N evaluated by molecular docking assay. The results would provide new guidance for anti-NSCLC new drug development based on the lead compound KW-2478.

Debio0932 is a promising lead compound in phase I clinical trials targeting the N-terminal ATP-binding pocket of the molecular chaperone heat-shock protein 90 (Hsp90N). The absence of a crystal structure of the Hsp90N-Debio0932 complex, however, has impeded further structural optimization of Debio0932 and understanding of the molecular-interaction mechanism. Here, a high-resolution crystal structure of the Hsp90N-Debio0932 complex was successfully determined (resolution limit 2.20 Å; PDB entry 6lr9) by X-ray diffraction and the molecular-interaction mechanism was analysed in detail, which suggested that Debio0932 suppresses cancer cells by accommodating itself in the ATP-binding pocket of Hsp90N, disabling its molecular-chaperone capability. The results of a thermal shift assay (ΔTm = 8.83 ± 0.90°C) and isothermal titration calorimetry (Kd = 15.50 ± 1.30 nM) indicated strong binding and favourable thermodynamic changes in the binding of Hsp90N and Debio0932. Based on the crystal structure of the complex and on molecular-interaction analysis, 30 new Debio0932 derivatives were designed and nine new derivatives exhibited increased binding to Hsp90N, as determined by molecular-docking evaluation. Additionally, Debio0932 suppressed cell proliferation (IC50 values of 3.26 ± 2.82 µM for A549, 20.33 ± 5.39 µM for H1299 and 3.16 ± 1.04 µM for H1975), induced cell-cycle arrest and promoted apoptosis in three non-small-cell lung cancer (NSCLC) cell lines. These results provide novel perspectives and guidance for the development of new anti-NSCLC drugs based on the lead compound Debio0932.

目的 通过虚拟筛选获得目标化合物,为靶向PARP14催化结构域抗肿瘤药物研发提供潜在先导化合物.方法 采用SYBYL-X 2.0软件对自主构建化合物库进行虚拟筛选,获得与靶标结合良好的目标化合物,分析其复合物模拟三维结构与分子互作机制.结果 成功获得14个目标化合物(Total score≥6分,Cscore≥4分),选取5个代表化合物,其主要通过氢键作用与PARP14催化结构域紧密联结.结论 成功获得14个目标化合物,为靶向PARP14催化结构域抗肿瘤药物研发提供潜在先导化合物.

<span id="ChDivSummary" name="ChDivSummary" class="abstract-text">心脑血管疾病是人类的死因之首,动脉粥样硬化（atherosclerosis,As）是其发生的病理基础。他汀类药物有明确的降血脂功效,可改善As,但其对某些高脂血症患者无效,长期使用可引发严重不良反应。烟酸（niacin,NA）可通过激动其受体GPR109A,产生独特降脂、抗炎、保护内皮作用,与他汀类联用,可明显改善As。该文从烟酸抗As作用、烟酸受体、新型受体激动剂、与他汀类联合用药四个方面,综述了烟酸与烟酸受体研究进展,以期为基于烟酸受体激动剂的抗As药物研发提供新思路。</span>

目的 采用虚拟筛选获得与靶标Hsp90N结合力较好的目标化合物,为抗肿瘤新药研发提供潜在先导化合物.方法 采用SYBYL软件对自主构建的化合物库进行虚拟筛选,获得目标化合物,采用精细对接,分析复合物模拟三维结构与分子互作机制.结果 通过虚拟筛选,成功获得21个目标化合物(Total score>6,Cscore≥4),其中Total score>8且Cscore≥4者18个,分别属于冬凌草甲素类、小檗碱类、巴马汀类、异长春花苷类、白桦酸类、香蕉皮类、榄香烯类、人参皂苷类和其他类化合物.综合考量Total score、Cscore打分值与结构多样性,选取5个最优化合物为代表,构建化合物与Hsp90N复合物模拟三维结构,分别为1号化合物2D_PeiLL(Total score=12.98,Cscore=4)、2号化合物XBJ_4463(Total score=12.78,Cscore=4)、4号化合物V12_ZhangYC(Total score=11.89,Cscore=4)、5号化合物1002483_WangTY(Total score=11.86,Cscore=4)和7号化合物S-9_LiZ(Total score=10.80,Cscore=5).结论 成功获得21个目标化合物,并阐明了5个最优代表的复合物模拟三维结构与分子互作机制,为靶向Hsp90N的新型抗癌药物研发提供潜在先导化合物.

Obtaining diffraction-quality crystals is still a bottleneck for biomacromolecular structure determination using X-ray diffraction. In practice, the bottleneck mainly comprises two aspects: difficulties in screening and in optimization, and both of them need screening kits. The paper aims at an investigation of the chemical components employed in 86 common commercial screening kits, and comparison with those in the Biological Macromolecules Crystallization Database (BMCD). First, the 86 screening kits are systematically analyzed in terms of design methods, classification, applicable scope, and manufacturing company. Second, the chemical components applied in these screening kits are investigated in detail in terms of the classification and utilization frequency, which are compared with those in BMCD. Third, four main chemical reagents of screening kits including salts, buffers, precipitants, and additives are analyzed in detail. The top ten utilized chemical components are listed. Last, the paper summarizes new progress and further innovation in crystallization condition screening practice and screening kits design. The analysis result would be a valuable reference for rational selection and design of screening kits, and even for personalized screening of a target biomacromolecule, which would provide new ideas to solve the bottleneck problem of biomacromolecular structure determination.

Poly-adenosine diphosphate-ribose polymerase (PARP) implements posttranslational mono- or poly-ADP-ribosylation modification of target proteins. Among the known 18 members in the enormous family of PARP enzymes, several investigations about PARP1, PARP2, and PARP5a/5b have been launched in the past few decades; more specifically, PARP14 is gradually emerging as a promising drug target. An intact PARP14 (also named ARTD8 or BAL2) is constructed by macro1, macro2, macro3, WWE, and the catalytic domain. PARP14 takes advantage of nicotinamide adenine dinucleotide (NAD+) as a metabolic substrate to conduct mono-ADP-ribosylation modification on target proteins, taking part in cellular responses and signaling pathways in the immune system. Therefore, PARP14 has been considered a fascinating target for treatment of tumors and allergic inflammation. More importantly, PARP14 could be a potential target for a chemosensitizer based on the theory of synthetic lethality and its unique role in homologous recombination DNA repair. This review first gives a brief introduction on several representative PARP members. Subsequently, current literatures are presented to reveal the molecular mechanisms of PARP14 as a novel drug target for cancers (e.g., diffuse large B-cell lymphoma, multiple myeloma, prostate cancer, and hepatocellular carcinoma) and allergic inflammatory. Finally, potential PARP inhibitor-associated adverse effects are discussed. The review could be a meaningful reference for innovative drug or chemosensitizer discovery targeting to PARP14.