4H-甲基咪唑苯二氮HIV-1抑制剂的定量构效关系研究

利用密度泛函理论计算了14种HIV抑制剂的4H-甲基咪唑苯二氮（TIBO）的分子性质。利用主成分分析（PCA）和聚类分析（HCA）减少了子变量的个数,从而使这些变量能有效地对抗HIV活性的4H-甲基咪唑苯二氮TIBO衍生物进行分类。主成分分析法表明,EH OMO、μ、LogP、Q A、QB和MR参数能够有效地把所研究的药物分为活性强的抗HIV病毒药物和活性弱的抗HIV病毒药物。聚类分析方法得到的结果与主成分分析得到的结果类似。为了检验结论是否正确,利用化学计量学方法,使用主成分分析法和分层聚类分析法对其他4个抗HIV活性的合成化合物进行了分析,其中3个被认为是活性强的抗HIV病毒药物,这与临床试验结果一致。主成分分析法和分层聚类分析法为新的抗HIV病毒的TIBO药物的分类提供了一个可信的规律。     

Key role of glutamic acid for the cytotoxic activity of the cyclotide cycloviolacin O2

Cyclotides are cyclic plant proteins with potent cytotoxic effects. Here we systematically probed the importance of surface-exposed charged amino acid residues of the cyclotide cycloviolacin O2, using a strategy involving chemical modifications. We show that the single glutamic acid plays a key role for the cytotoxicity: methylation of this residue produced a 48-fold decrease in potency. Virtually no change in potency was observed when masking the single arginine residue using 1,2-cyclohexanedione, while acetylation of the two lysine residues reduced the potency 3-fold. The derivative with modifications at both arginine and lysine residues showed a 7-fold loss of potency. In addition, we show that the activity is dependent on an intact disulfide network and that the short sequences between the six cysteine residues, that is, the backbone loops, are devoid of cytotoxic activity. Received 11 October 2005; received after revision 3 November 2005; accepted 15 November 2005     

Synthesis, structure-activity relationship of nociceptin and its fragments

Nociceptin (NC) and its 4 fragments have been synthesized by solid phase peptide synthesis. Their hypertensive activity and mechanism, MVD assay and structure-activity relationship have been investigated. Results show that NC(1-13)NH2 is the smallest fragment that shares the same activity with NC. The truncation of C-terminal not only leads the decrease of receptor affinity but also the changes of receptor selectivity. The entire sequence may not be required for the full activity since NC(1-13)NH2 is as active as NC. Arg-Lys at the 12-13 position of C-terminal plays an important role in the activity of NC. The hypotensive activity of NC does not antagonize the hypertensive activity of renin-angiotensin system.     

一类新型6-烷氨基-2-烷硫基嘌呤核苷衍生物抗血小板凝集的3D-QSAR研究

通过自组织分子场分析（SOMFA）方法,对20个具有测试活性的2-烷硫基-6-烷氨基嘌呤核苷衍生物进行三维定量构效关系（3D-QSAR）研究,得到预测能力最佳的SOMFA模型,其中交叉验证系数r_cv²=0.801,非交叉验证系数r²=0.807,统计方差比F=75.281,标准方差s=0.130。同时,通过对该模型的立体场和静电场三维网格图进行分析,能够较清晰直观地为设计新型的高活性抗血小板药物分子提供理论指导。     

Combining docking and comparative molecular similarity indices analysis （COMSIA） to predict estrogen activity and probe molecular mechanisms of estrogen activity for estrogen compounds

Estrogen compounds are suspected of disrupting endocrine functions by mimicking natural hormones, and such compounds may pose a serious threat to the health of humans and wildlife. Close attention has been paid to the prediction and molecular mechanisms of estrogen activity for estrogen com- pounds. In this article, estrogen receptor a subtype （ERa） -based comparative molecular similarity indices analysis （COMSIA） was performed on 44 estrogen compounds with structural diversity to find out the structural relationship with the activity and to predict the activity. The model with the significant correlation and the best predictive power （R^2= 0.965, Q^2 LOO： 0.599, R^2 pred ： 0.825） was achieved. The COMSIA and docking results revealed the structural features for estrogen activity and key amino acid residues in binding pocket, and provided an insight into the interaction between the ligands and these amino acid residues.     

自组织神经树用于芬太尼衍生物构效关系的研究

运用自组织神经树方法研究了芬太尼衍生物的镇痛活性与其结构特征参数间的非线性关系，结果表明，该网络性能良好，识别成功率较高，可望成为药物构效关系研究的有效辅助手段。     

Analysis of structural features responsible for the sweetness of the sesquiterpene,hernandulcin

Summary The relationship between sweetness and structure was studied for several analogues of the intensely sweet sesquiterpene, hernandulcin. These derivatives were prepared synthetically, and were subjected to spectroscopic and conformational analysis. With the exception of the parent substance, none of the derivatives tested proved to be sweet. Evidence gathered in this study suggests that hernandulcin binds to its putative receptor through a three-point interaction, involving the C-1 carbonyl and C-1 hydroxyl groups, and the double bond between C-4 and C-5. In the course of a preliminary safety assessment, the 3-desmethyl derivative of hernandulcin was found to be mutagenic towardSalmonella typhimurium strain TM677.Acknowledgments. We thank Drs A. J. Hopfinger and R. Pearlstein for helpful suggestions concerning the use of CHEMLAB software, and Mr E. F. Robbins of the Research Resources Center, University of Illinois at Chicago for helpful assistance with the MS determinations. During the course of this investigation, one of us (C.M.C.) was affiliated with the Department of Pharmacology, University of Illinois College of Medicine, Chicago, Illinois, and the gratefully acknowledges the support and encouragement of the late Professor Martin P. Schulman. J. M. P. is the recipient of a Research Career Development Award from the National Cancer Institute (1984–1989).Paper 14 in the series Potential Sweetening Agents of Plant Origin. For paper 13, see Nanayakkara, N. P. D., Hussain, R. A., Pezzuto, J. M., Soejarto, D. D. and Kinghorn, A. D., J. med. Chem., in press.     

Cantharidin analogues and their attractancy for ceretopogonid flies (Diptera: Ceratopogonidae)

Several ceratopogonid flies are attracted to cantharidin and ingest it from both cantharidin-baits and from meloid beetles, one of the few known natural sources for cantharidin. Because meloids are absent in northern Bavaria, and certain canthariphilous flies of the genusAtrichopogon are temporarily associated with certain plants (Apiaceae, Aristolochiaceae), it was suggested that canthariphilous ceratopogonids might be generally attracted by chemically similar plant-derived compounds. At first the seasonal fluctuating attractancy, sex ratio and behaviour ofA. oedemerarum Storå was studied at cantharidin baits. Synthetic cantharidin analogues exhibited an attractancy forA. oedemerarum if the exo,exo-7-oxabicyclo[2.2.1]heptane skeleton of cantharidin was associated with a 2,3-dicarboxylic anhydride or a 2,3--lactone. According to structure-activity studies, the analogues seem to fit best into the active site of the receptor if the carbonyl function of the -lacton is in the exo- and 2-position. This is the first report indicating that molecules other than cantharidin are attractive for canthariphilous insects.     

2-羟基-3-烷基-1,4-萘醌除草活性的QSAR研究

利用量子化学程序计算了23个2-羟基-3-烷基-1,4-萘醌化合物的量子化学参数(如:最高占据轨道能级、最低空轨道能级、极化率、氧原子静电荷、偶极矩、生成热、水化能、脂水分配系数),并对化合物对光系统Ⅱ(PSⅡ)的抑制活性进行了定量结构-活性相关(Q SAR s)分析,其中生成热、水化能、脂水分配系数、极化度四个参数共同构建的多元二阶模型准确性最高(R=0.897,F=11.026).通过该模型可推测活性大小主要取决于它们从水相迁移到生物相的难易程度以及与生物体靶位发生色散作用(疏水作用)的能力.