De novo design of VEGFR-2 tyrosine kinase inhibitors based on a linked-fragment approach

Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors have been demonstrated to possess substantial antitumor activity. VEGFR-2 tyrosine kinase inhibitors are crucial for development of antitumor drugs. Based on the crystal structure of VEGFR-2 tyrosine kinase, a linked-fragment strategy was employed to design novel VEGFR-2 tyrosine kinase inhibitors, and 1000 compounds were generated in this process. Absorption, distribution, metabolism, excretion and toxicity (ADMET) were used to screen the 1000 compounds, and 59 compounds were acceptable. Scaffold hopping was then used for further screening, and only four compounds were obtained in this way. Then, the binding energy of the four molecules to VEGFR-2 tyrosine kinase was calculated using molecular docking, and their values were found to be lower than that of Sorafenib. Finally, molecular dynamics simulations were performed on the complex of the compound with the lowest binding energy with VEGFR-2 tyrosine kinase, and the binding model was analyzed. At the end, four chemical entities with novel structures were obtained, and were suggested for experimental testing in future studies.     

7β-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues

With the purpose of identifying novel selective κ opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7β-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7β-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7β-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7β-methyl orvinol analogues. Surprisingly, SLL-603, a 7β-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7β-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations.     

莎车巴旦姆物候期对气象条件的响应及花期预测模型

利用莎车县农业气象试验站2008—2013年巴旦姆物候期和同期气象观测资料,分析了巴旦姆物候期的变化特征以及气温、日照时数对物候期的影响.结果表明：巴旦姆花期之前的物候期始日之间均呈正相关,与花期之后的物候期始日的相关性大多较小,花芽膨大早迟与休眠期、生长期天数分别呈极显著的正相关和负相关.以果实成熟期为界,气温对之前、之后物候期间隔日数的影响分别为负相关和正相关,日照时数与物候期间隔日数大多为正相关.果实成熟 叶变色始期间隔日数对平均最高气温以及花序出现 开花末期、叶变色始期 落叶末期间隔日数对日照时数存在明显的响应.当巴旦姆休眠期符合日平均气温-3.0～-7.5 ℃的天数满30 d后,经过17～28 d将进入花芽萌动期.花芽萌动期、开花始期、叶变色始期和落叶末期的始日分别与首个候平均气温≥4 ℃且候平均最高气温≥12 ℃、春季侯平均气温≥14 ℃且侯平均最高气温≥22 ℃、秋季首个侯平均气温≤10 ℃且侯平均最高气温≤18 ℃和冬季首个侯平均气温≤1.9 ℃的候序一一对应.利用偏最小二乘法回归分析,建立巴旦姆盛花期始日预测模型,经过检验模型效果较好.     

Exploration of Novel MTH1 Inhibitors Using Fragment-Based De Novo Design,Virtual Screening,and Reverse Virtual Screening Methods

Russian Journal of Bioorganic Chemistry - MTH1 (MutT homologue 1, NUDT1), a member of the Nudix phosphohydrolase superfamily of enzymes, was speculated to contribute to hampering tumor growth based...     

适宜河北省旱寒区的冬油菜品种的筛选

筛选适宜河北省低平原地区种植的油菜品种,同时实现生态效益和经济效益,为相似气候区油菜品种的种植选择及种植结构的调整提供理论依据。以16个油菜品种为材料,对品种间农艺性状的变化进行方差分析、相关性分析和聚类分析。各品种间分枝部位存在差异,变异系数为61.82%,品种JR5分枝部位最低,14T×38最高;其次差异较为明显的是产量和二次分枝数,变异系数分别为26.69%和24.89%,14T×38产量最高,20SY-13最低。二次分枝数最大和最小的品种分别为20SY-13和天油142。油菜产量与一次分枝数和主花序角果数呈极显著正相关(P<0.01),株高与分枝部位、主花序长度和主花序角果数呈显著正相关关系,一次分枝数与主花序角果数呈显著正相关(P<0.05),二次分枝数与主花序角果数呈极显著负相关。当欧式距离为5时,16个油菜品种可分为五大类。选择株高较高、一次分枝数和主花序角果数较多、二次分枝数较少且可以在当地正常越冬的油菜品种进行种植,可以获得较高水平产量;20SY-13在当地秋季种植应注意安全越冬。     

抗厌氧菌中草药的系列研究：Ⅰ,抗厌氧菌中草药的筛选

目前治疗厌氧菌感染的药物不够理想,仍需发掘新药。根据文献选出抗感染中草药389种,用水、乙醇和石油醚三种溶剂,分别提取和制备成含生药1g/ml的药液,对临床常见的脆弱类杆菌等12种厌氧菌进行平板打孔法的抑菌试验。结果显示诃子、茴香根、穿心莲、黄连、肉桂、大黄、五味子、木通等53种中草药的1～3种提取液能对二种以上的厌氧菌有直径20mm以上的抑菌环。反复试验显示肉佳、大黄、五味子、木通能稳定地对4种以上的厌氧菌有20mm以上的抑菌环。作者认为平板打孔法是筛选中草药抗菌作用的简便方法,并准备对选出的中草药作进一步研究。