基于FGFR1靶点分子虚拟对接筛选淫羊藿中抗骨质疏松的药效成分

目的基于FGFR1蛋白靶点筛选淫羊藿中抗骨质疏松的药效成分。方法采用维甲酸灌胃14 d复制大鼠骨质疏松模型,给予淫羊藿提取物进行干预;采用Western blotting法检测各组大鼠股骨FGFR1蛋白的表达,用UPLC-Q-TOF-MS确认提取物中化学成分。基于FGFR1靶点进行分子虚拟对接筛选药效成分。结果淫羊藿能够改善大鼠骨质疏松症状,并提高FGFR1蛋白的表达。淫羊藿提取物中指认出23种化合物,其中淫羊藿苷、淫羊藿次苷I、箭藿苷C可与FGFR1可以有效对接。结论淫羊藿中淫羊藿苷、淫羊藿次苷I、箭藿苷C可能通过上调FGFR1发挥抗骨质疏松作用。     

乳腺癌诊断剂PET分子探针的研究进展

乳腺癌已成为危及女性生命健康最常见的恶性肿瘤之一,若能实现对其进行早期诊断并积极干预,会极大提高患者的生存率。近几十年来,核素功能成像特别是PET成像显著提高了对乳腺癌各种生物学过程的认识能力,为从分子及细胞水平准确地诊断乳腺癌提供了可能。目前已有多种乳腺癌PET分子探针被开发,对代谢类、细胞增殖类、雌激素α受体类、雌激素β受体类、孕激素受体类、表皮生长因子类、胃泌素释放肽类、乏氧类、氨基转运类PET分子探针的研究进展进行综述。     

葛根素抑制钠-葡萄糖协同转运蛋白2活性发挥促尿糖作用研究

目的 研究葛根素通过抑制钠-葡萄糖协同转运蛋白2（SGLT2）发挥促尿糖、降血糖作用。方法 同源模建获得SGLT2蛋白虚拟结构,以达格列净为阳性药,与葛根素进行分子对接,考察其分子结合强弱;采用能稳定表达人SGLT2（hSGLT2）蛋白的中国仓鼠卵巢（CHO）细胞、以^14C-甲基葡萄糖苷（[^14C]-AMG）为底物,评价葛根素体外抑制SGLT2的活性;以达格列净为阳性药,采用大鼠体内口服糖耐量试验（OGTT）和尿排泄糖试验（UGE）观察葛根素直接降血糖和促尿糖活性。结果 分子对接得分显示,葛根素是SGLT2的底物,总体作用强度不及达格列净;体外实验显示,葛根素可较强抑制hSGLT2,最大效应为84%左右,半数抑制浓度（IC₅₀）为0.40 μmol/L;OGTT结果显示,葛根素10、30、60和120 mg/kg剂量的抑糖率分别为5.1%、6.5%、16%和22%,呈剂量相关性;在UGE实验中,随着葛根素剂量的增大,尿糖量增加,与模型组比较,30、60和120 mg/kg剂量组差异显著（P<0.05、0.01）。结论 葛根素具有抑制hSGLT2、促尿糖降低血糖的药理活性,有可能作为一类新型结构的SGLT2抑制剂的先导化合物。     

Elastin-like polypeptides: the power of design for smart cell encapsulation

Introduction: Cell encapsulation technology is still a challenging issue. Innovative methodologies such as additive manufacturing, and alternative bioprocesses, such as cell therapeutic delivery, where cell encapsulation is a key tool are rapidly gaining importance for their potential in regenerative medicine. Responsive materials such as elastin-based recombinant expression products have features that are particularly attractive for cell encapsulation. They can be designed and tailored to meet desired requirements. Thus, they represent promising candidates for the development of new concept-based materials that can be employed in this field.

Areas covered: An overview of the design and employment of elastin-like polypeptides for cell encapsulation is given to outline the state of the art. Special attention is paid to the design of the macromolecule employed as well as to the method of matrix formation and the biological system involved.

Expert opinion: As a result of recent progress in regenerative medicine there is a compelling need for materials that provide specific properties and demonstrate defined functional features. Rationally designed materials that may adapt according to applied external stimuli and that are responsive to biological systems, such as elastin-like polypeptides, belong to this class of smart material. A run through the components described to date represents a good starting point for further advancement in this area. Employment of these components in cell encapsulation application will promote its advance toward ‘smart cell encapsulation technology’.     

Rational excipient selection for co-amorphous formulations

Introduction: For almost two decades there has been intense debate about whether the amorphous solid state form could resolve the solubility problems and subsequent bioavailability issues of many small molecule drugs. Since the amorphous form is a high energy and unstable state of solid matter, any material in that form requires stabilization.

Areas covered: This review examines the technologies being exploited to stabilize the amorphous state in co-amorphous formulations. The review emphasizes the importance of the appropriate selection criteria of stabilizing excipient and focuses on the mechanisms of stabilization.

Expert opinion: An extensive literature review has revealed that the current research seeking to achieve stabilization of an amorphous form tends to be conducted on a case-by-case basis. This kind of approach is very inefficient since it can rarely be transferred to other cases. The greatest weakness in the selection of stabilizing excipient for co-amorphous formulations is that modern computational tools have rarely been utilized as a predictive tool in the selection of the excipient. It is evident that more research needs to be done to study larger datasets with modern in silico tools, chemometrics and advanced statistical tools to achieve a more predictive, and systematic approach for the screening of stabilizing excipients to be incorporated into co-amorphous formulations.     

红色荧光蛋白变种mCherry的表达、纯化和应用探讨

目的 应用pET表达系统原核表达红色荧光蛋白变种mCherry,分析重组mCherry表达与荧光变化的关系,为其纯化及作为原核报告系统应用提供依据.方法 根据GenBank中收录的mCherry氨基酸序列合成其编码基因,构建pET-mCherry表达质粒,转化入大肠埃希菌BL21 (DE3)表达宿主.在不同诱导时间点,考察菌株荧光强度、mCherry表达量、培养上清液mCherry泄漏情况.诱导10h后提取重组mCherry,利用荧光强度估算提取收率,并通过凝胶电泳分析提取液的蛋白纯度.结果 成功构建pET-mCherry表达载体,并在BL21(DE3)中得到高效诱导表达.荧光检出滞后于mCherry的表达,随诱导时间延长重组mCherry不断泄漏至培养液中.初步提取的重组mCherry纯度达到95％以上.结论 应用pET表达系统可高效表达mCherry,过表达mCherry可泄漏至胞外,方便其纯化.mCherry作为原核报告系统应用时,合理的诱导时间可能是关键影响因素.     

In silico strategies on prion pathogenic conversion and inhibition from PrPC –PrPSc

Introduction: To date, various therapeutic strategies identified numerous anti-prion compounds and antibodies that stabilize PrP^C, block the conversion of PrP^C-PrP^Sc and increased effect on PrP^Sc clearance. However, no suitable drug has been identified clinically so far due to the poor oral absorption, low blood–brain-barrier [BBB] penetration, and high toxicity. Although some of the drugs were proven to be effective in prion-infected cell culture and whole animal models, none of them increased the rate of survival compared to placebo.

Areas covered: In this review, the authors highlight the importance of in silico approaches like molecular docking, virtual screening, pharmacophore analysis, molecular dynamics, QSAR, CoMFA and CoMSIA applied to detect molecular mechanisms of prion inhibition and conversion from PrP^C-PrP^Sc.

Expert opinion: Several in silico approaches combined with experimental studies have provided many structural and functional clues on the stability and physiological activity of prion mutants. Further, various studies of in silico and in vivo approaches were also shown to identify several new small organic anti-scrapie compounds to decrease the accumulation of PrP^res in cell culture, inhibit the aggregation of a PrP^C peptide, and possess pharmacokinetic characteristics that confirm the drug-likeness of these compounds.     

Design,synthesis, and preliminary bioactivity evaluation of N1‐hydroxyterephthalamide derivatives with indole cap as novel histone deacetylase inhibitors

Histone deacetylases inhibitors (HDACIs) have been widely recognized as significant therapeutic approach to cancers. In our efforts to develop novel histone deacetylases inhibitors (HDACIs) as potential anticancer agents, a series of N¹‐hydroxyterephthalamide derivatives with an indole cap group were designed and synthesized. Compound 12m was identified to be the most potent one (IC₅₀ = 0.074 μm against HeLa nuclear extract ) and showed higher inhibitory activity than the positive control SAHA (IC₅₀ = 0.131 μm ), which was also verified by further molecular docking studies into active site of HDAC2. The results of selectivity on the inhibition of HDACs exhibited 12m being with similar isoform selective profile with PXD101. In addition, the representative compounds (8d, 12d, 12j, 12m) based on the outcomes of preliminary tumor cell screening demonstrated more potent or comparable to SAHA in the next antiproliferative activity assays. Collectively, the results encouraged further development of this chemical template to provide more potent analogs as HDACIs.     

New insights into the structure of the trace amine‐associated receptor 2: Homology modelling studies exploring the binding mode of 3‐iodothyronamine

Recent studies have further investigated the trace amine‐associated receptor type 2 (TAAR2) pharmacology, revealing its role not only at the olfactory sensory neurons but also at the immune system, being expressed in human leucocytes. In particular, the ability of this receptor to bind the unselective TAAR ligand 3‐iodo‐thyronamine ( T ₁ AM ) was elucidated, making in the meanwhile the discovery of selective compounds a urgent need to derive much more suitable tools for studying TAARs. In this context, we developed our work on TAAR2 applying a structure‐based computational protocol, including TAAR2 homology modelling and T ₁ AM docking studies. The results were compared with those we previously obtained about TAAR1, in order to point out new insights guiding for selectivity between TAAR1 and TAAR2. The in silico strategy applied allowed us to provide for the first time thorough TAAR2 homology models, which are expected to be useful tools for a further design process of more selective TAAR ligands.