Structure-based virtual screening of natural products as potential stearoyl-coenzyme a desaturase 1 (SCD1) inhibitors

Stearyl coenzyme A desaturase enzyme 1 (SCD1) is a key enzyme that catalyzes the conversion of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA) and plays a vital role in lipid metabolism of tumor cells. SCD1 is overexpressed in a variety of malignant tumors, and its related inhibitors showed significant anti-tumor activity in vitro and in vivo experiments, which is a new target for tumor therapy. The focus of this study is to identify novel SCD1 inhibitors from natural products through computer simulations. First, 176,602 compounds from natural product databases were virtually screened. By molecular dynamics (MD) simulations, the ligand-protein interactions of 5 compounds with high docking manifestation were analyzed accurately. Then, MM-GBSA and MM-PBMA methods were used to verify the results. Finally, ADMET prediction was performed for the 5 compounds. As a result, two natural products with potential inhibition towards SCD1 were identified, which had the excellent docking manifestation, binding mode within SCD1 pocket and stability during molecular dynamics simulation. This study provides a meaningful model for the development and optimization of new inhibitors and anti-tumor drugs targeting SCD1.     

Structure-based virtual screening of influenza virus RNA polymerase inhibitors from natural compounds: Molecular dynamics simulation and MM-GBSA calculation

The resistances of matrix protein 2 (M2) protein inhibitors and neuraminidase inhibitors for influenza virus have attracted much attention and there is an urgent need for new drug. The antiviral drugs that selectively act on RNA polymerase are less prone to resistance and possess fewer side effects on the patient. Therefore, there is increased interest in screening compounds that can inhibit influenza virus RNA polymerase. Three natural compounds were found by using molecular docking-based virtual screening, which could bind tightly within the polymerase acidic protein-polymerase basic protein 1 (PA-PB1) subunit of influenza virus polymerase. Firstly, their drug likeness properties were evaluated, which showed that the hepatotoxicity values of all the three compounds indicating they had less or no hepatotoxicity, and did not have the plasma protein biding (PPB) ability, the three compounds needed to be modified in some aspects, like bulky molecular size. The stability of the complexes of PA-hits was validated through molecular dynamics (MD) simulation, revealing compound 2 could form more stable complex with PA subunit. The torsional conformations of each rotatable bond of the ligands in PA subunit were also monitored, to investigate variation in the ligand properties during the simulation, compound 3 had fewer rotatable bonds, indicating that the molecule had stronger rigidity. The bar charts of protein–ligand contacts and contacts over the course of trajectory showed that four key residues (Glu623, Lys643, Asn703 and Trp706) of PA subunit that participated in hydrogen-bond, water bridge and hydrophobic interactions with the hit compounds. Finally, the binding free energy and contributed energies were calculated by using MM-GBSA method. Out of the three compounds, compound 1 showed the lowest total binding free energy. Among all the interactions, the contribution of the covalent binding and the van der Waals energy were more than other items, compound 1 formed more stable hydrogen bonds with the residues of PA subunit binding pocket. This study smoothed the path for the development of novel lead compounds with improved binding properties, high drug likeness, and low toxicity to humans for the treatment of influenza, which provided a good basis for further research on novel and effective influenza virus PA-PB1 interaction inhibitors.     

In Vitro Anti-Diabetic Activities and UHPLC-ESI-MS/MS Profile of Muntingia calabura Leaves Extract

Anti-diabetic compounds from natural sources are now being preferred to prevent or treat diabetes due to adverse effects of synthetic drugs. The decoction of Muntingia calabura leaves was traditionally consumed for diabetes treatment. However, there has not been any published data currently available on the processing effects on this plant’s biological activity and phytochemical profile. Therefore, this study aims to evaluate the effect of three drying methods (freeze-drying (FD), air-drying (AD), and oven-drying (OD)) and ethanol:water ratios (0, 50, and 100%) on in vitro anti-diabetic activities of M. calabura leaves. In addition, an ultrahigh-performance-liquid chromatography–electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) method was used to characterize the metabolites in the active extract. The FD M. calabura leaves, extracted with 50% ethanol, is the most active extract that exhibits a high α-glucosidase and α-amylase inhibitory activities with IC₅₀ values of 0.46 ± 0.05 and 26.39 ± 3.93 µg/mL, respectively. Sixty-one compounds were tentatively identified by using UHPLC-ESI-MS/MS from the most active extract. Quantitative analysis, by using UHPLC, revealed that geniposide, daidzein, quercitrin, 6-hydroxyflavanone, kaempferol, and formononetin were predominant compounds identified from the active extract. The results have laid down preliminary steps toward developing M. calabura leaves extract as a potential source of bioactive compounds for diabetic treatment.     

高效液相色谱法测定原油脱钙工艺排水体系中NS-3缓蚀剂浓度

将反相高效液相色谱法用于原油脱钙工艺排水体系中缓蚀剂浓度测定研究,建立了缓蚀剂的快速分离检测方法.使用C18柱,以乙腈∶二氯甲烷=9∶1(V/V)混合溶剂为流动相,采用紫外检测器在300 nm处对排水体系中的缓蚀剂进行测定,外标法进行定性定量分析.测定结果表明缓蚀剂浓度在100~900 mg/kg时其峰面积与相应的质量浓度有良好的线性关系,其线性相关系数为0.999 9,相对标准偏差(RSD)和相对误差(RD%)都小于2.0%.用二氯甲烷为萃取剂对排水体系中的缓蚀剂进行萃取,其平均回收率为100%±2%.最低检测线为0.75mg/kg.该方法具有测定结果准确可靠,操作简便快速,重现性好等特点.     

Effects of Roxadustat on Erythropoietin Production in the Rat Body

Anemia is a major complication of chronic renal failure. To treat this anemia, prolylhydroxylase domain enzyme (PHD) inhibitors as well as erythropoiesis-stimulating agents (ESAs) have been used. Although PHD inhibitors rapidly stimulate erythropoietin (Epo) production, the precise sites of Epo production following the administration of these drugs have not been identified. We developed a novel method for the detection of the Epo protein that employs deglycosylation-coupled Western blotting. With protein deglycosylation, tissue Epo contents can be quantified over an extremely wide range. Using this method, we examined the effects of the PHD inhibitor, Roxadustat (ROX), and severe hypoxia on Epo production in various tissues in rats. We observed that ROX increased Epo mRNA expression in both the kidneys and liver. However, Epo protein was detected in the kidneys but not in the liver. Epo protein was also detected in the salivary glands, spleen, epididymis and ovaries. However, both PHD inhibitors (ROX) and severe hypoxia increased the Epo protein abundance only in the kidneys. These data show that, while Epo is produced in many tissues, PHD inhibitors as well as severe hypoxia regulate Epo production only in the kidneys.     

Conjugation of Palbociclib with MHI-148 Has an Increased Cytotoxic Effect for Breast Cancer Cells and an Altered Mechanism of Action

The CDK4/6 inhibitor palbociclib, combined with endocrine therapy, has been shown to be effective in postmenopausal women with estrogen receptor-positive, HER2-negative advanced or metastatic breast cancer. However, palbociclib is not as effective in the highly aggressive, triple-negative breast cancer that lacks sensitivity to chemotherapy or endocrine therapy. We hypothesized that conjugation of the near-infrared dye MHI-148 with palbociclib can produce a potential theranostic in triple-negative, as well as estrogen receptor-positive, breast cancer cells. In our study, the conjugate was found to have enhanced activity in all mammalian cell lines tested in vitro. However, the conjugate was cytotoxic and did not induce G1 cell cycle arrest in breast cancer cells, suggesting its mechanism of action differs from the parent compound palbociclib. The study highlights the importance of investigating the mechanism of conjugates of near-infrared dyes to therapeutic compounds, as conjugation can potentially result in a change of mechanism or target, with an enhanced cytotoxic effect in this case.     

Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR)

As one of the key phosphatidylinositol 3-kinase-related kinases (PIKKs) family members, ataxia telangiectasia and RAD3-related protein kinase (ATR) is crucial in maintaining mammalian cell genomic integrity in DNA damage response (DDR) and repair pathways. Dysregulation of ATR has been found across different cancer types. In recent years, the inhibition of ATR has been proven to be effective in cancer therapy in preclinical and clinical studies. Importantly, tumor-specific alterations such as ATM loss and Cyclin E1 (CCNE1) amplification are more sensitive to ATR inhibition and are being exploited in synthetic lethality (SL) strategy. Besides SL, synergistic anticancer effects involving ATRi have been reported in an increasing number in recent years. This review focuses on the recent advances in different forms of synergistic antitumor effects, summarizes the pharmacological benefits and ongoing clinical trials behind the biological mechanism, and provides perspectives for future challenges and opportunities. The hope is to draw awareness to the community that targeting ATR should have great potential in developing effective anticancer medicines.     

以gp41为靶标的小分子-多肽缀合物作为HIV-1融合抑制剂的设计、合成及活性初筛

芳基吡咯类小分子化合物NB-2衍生物(Noc或Npc)与衍生于C34中的靶标特异性多肽P26所形成的缀合物具有低纳摩尔水平的融合抑制活性.本文通过不同长度或不同柔性的连接臂将Noc或Npc与衍生于C34的靶标特异性多肽P27缀合,探讨了C34中a位残基I635和连接臂对缀合物活性的影响.人体免疫缺陷病毒1型(HIV-1)Env介导的细胞-细胞融合实验结果表明,多肽与小分子之间产生了强的协同作用.     

氯化2,3,5-三苯基-2 氢-四唑(TTC)及2,4,6-三(2-吡啶基)-s -三嗪(TPT)在1mol/L HCl 中对Q235碳钢的缓蚀作用及机理的研究(Ⅱ)

通过X射线光电子能谱(XPS)、椭圆偏振原位测试考察了氯化2,3,5-三苯基-2H-四唑(TTC), 2,4,6-三(2-吡啶基)-s-三嗪(TPT)分子在1 mol/L HCl中对碳钢表面的缓蚀作用, 并从微观上对二者的缓蚀机理进行探讨. XPS测试结果显示, 由C, N元素的1s特征峰产生的化学位移及其积分峰面积表明TTC, TPT分子在金属表面产生了有效抑制腐蚀的保护层; 由椭圆偏振原位测试并结合动电位极化曲线测试,考察了TTC, TPT分子对金属表面腐蚀反应的抑制程度, 并得到了相位差等参量, 结果表明二者在金属表面形成了具有缓蚀作用的覆盖层.     

基于药效团模型的DHODH抑制剂构效关系研究

利用药效团模型研究二氢乳清酸脱氢酶(Dihydroorotate dehydrogenase,DHODH)抑制剂的构效关系,为DHODH抑制剂的虚拟筛选提供新的方法.以31个具有DHODH抑制活性的化合物为训练集化合物,半数抑制浓度(IC50)范围为7~63000 nmol/L,利用Catalyst/HypoGen算法构建DHODH抑制剂药效团模型,通过对训练集化合物多个构象进行叠合,提取药效团特征及三维空间限制构建药效团模型.利用基于CatScramble的交叉验证方法及评价模型对已知活性化合物的活性预测能力,确定较优药效团模型.模型包含1个氢键受体、3个疏水中心,表征了受体配体相互作用时可能发生的氢键相互作用、疏水相互作用和π-π相互作用,4个药效特征在三维空间的排列概括了DHODH抑制剂产生活性的结构特点.所得较优模型对训练集化合物及测试集化合物的计算活性值与实验活性值的相关系数分别为0.8405和0.8788.利用药效团模型对来源于微生物的系列化合物进行虚拟筛选,筛选出59个预测活性较好的化合物,可作为进一步药物研发的候选化合物.