趋化因子受体CXCR4非肽类抑制剂药效团的设计

趋化因子受体CXCR4是HIV进入宿主细胞的辅助受体之一.为了研究其抗HIV抑制剂的构效关系,6个结构多样性和拥有高活性的抑制剂被作为训练集来构建药效团模型,然后对由活性抑制剂和非活性抑制剂构成的测试集进行筛选,通过应用受试者工作特征(receiver operator characteristic,ROC)曲线和计算富集因子(enrichment factor,EF)的方法评估每个模型的预测能力与合理性.最终得到一个具有较高的ROC曲线下面积(area under curve,AUC)与富集因子的药效团模型,可用于指导新颖CXCR4抑制剂的设计及相关抗艾滋病药物的研发.     

Strategies for the design of inhibitors of aldose reductase, an enzyme showing pronounced induced-fit adaptations

Aldose reductase is involved in the polyol pathway, catalyzing the reduction of glucose to sorbitol. However, due to pronounced binding site adaptations, the enzyme can operate on a broad palette of structurally diverse substrates ranging from small aliphatic and aromatic aldehydes up to steroid-type ligands. A comparative analysis of the presently accessible crystal structures of aldose reductase complexes reveals four binding-competent protein conformations. Additional relevant conformers are detected through molecular dynamics simulations. They indicate an equilibrium of several conformers which is shifted towards the binding-competent geometries upon ligand binding. Such a manifold system with several alternative binding site conformers requires some tailored concepts in virtual screening. We followed two strategies, both successfully suggesting new micromolar inhibitors. In a first attempt, we concentrated on one preferred conformer and performed a virtual screening, assuming that the binding pocket of aldose reductase adopts only this conformation. In a second approach, we followed a ligand superpositioning method. Ligands were extracted in their bound conformations from three different crystal structures, all accommodating the ligands with different active site conformations. After merging these ligands into one supermolecule, mutual alignments were computed, taking candidate ligands from a screening database. The latter strategy also retrieved several structurally new inhibitors of micromolar potency.     

一类双氯芬酸类似物环氧合酶抑制剂作用模式的理论研究

基于 1PXX 晶体结构以及以晶体中双氯芬酸 DIF701 为模版的双氯芬酸类似物2型环氧合酶(COX-2) 抑制剂的结构,利用药效团和自组织分子力场分析方法,探讨了 COX-2 与抑制剂的相互作用模式。建立了双氯芬酸药效团模型和 COX-2 抑制剂三维定量构效关系模型,并且两种方法所得的模型吻合;确定的 COX-2 与抑制剂的作用模式,可以指导抑制剂的设计,用于开发抗炎药物。     

药物开发软件Catalyst及其在计算机辅助药物设计中的应用

计算机辅助药物设计(CADD)是一门多学科交叉的边缘学科,在新药研发,特别是在先导化合物的发现和优化过程中发挥着越来越重要的作用。Catalyst是一种基于药效团模型的综合性药物开发软件。本文着重介绍了Catalyst软件的基本功能及其在新药筛选中的应用。     

基于蛋白质药效团匹配的化合物功能预测

采用了基于蛋白质药效团匹配的化合物评价策略.以配体分子为提问结构对相应数据库进行反向筛选,根据筛选结果可以得到提问分子在人体内可能的作用受体,并以此为依据进行分子结构改造,以加强配体分子的结合专一性.选取环氧合酶2的专一性抑制剂Rofecoxib按照药效团匹配方法进行反向筛选评价,结果与实验事实吻合,并且提出了一个Rofecoxib的潜在靶标.此方法为未知化合物的功能预测和"老药新用"提供了一种新方法、新思路.     

川陈皮素潜在药效靶标预测及多维药理作用分析

目的预测中药活性成分川陈皮素的潜在靶标并进行分子对接验证,探讨其多维药理作用。方法运用反向分子对接服务器PharmMapper将川陈皮素与2241个人类蛋白靶标分别对接,选取Normalized Fit Score打分值前15的靶蛋白,采用Systemsdock Web Site平台对具有疾病治疗价值的主要靶蛋白进行正向分子对接验证。结果川陈皮素与成纤维细胞激活蛋白(Seprase)、网织红细胞-4受体(Reticulon-4 recoptor)、组织蛋白酶L2(CathepsinL2)3个靶蛋白结合较好,对接分数分别为5.215、5.227、6.090。靶蛋白药效团模型与川陈皮素分子特征一致,分子对接显示川陈皮素与靶蛋白核心氨基酸有相互作用。结论川陈皮素与Seprase、Reticulon-4 recoptor、CathepsinL23个重要靶蛋白结合强度较好,具有抗癌、抗氧化、抗炎、抗血栓形成等药理作用。     

The short proline-rich antibacterial peptide family

From the many peptide families that are induced upon bacterial infection and can be isolated from all classes of animals, the short, proline-rich antibacterial peptides enjoy particular interest. These molecules were shown to inactivate an intracellular biopolymer in bacteria without destroying or remaining attached to the bacterial cell membrane, and as such emerged as viable candidates for the treatment of mammalian infections. These peptides were originally isolated from insects, they kill mostly Gram-negative bacteria with high efficiency and they show structural similarities with longer insect- and mammal-derived antimicrobial peptides. However, while the distant relatives appear to carry multiple functional domains, apidaecin, drosocin, formaecin and pyrrhocoricin consist of only minimal determinants needed to penetrate across the cell membrane and bind to the target biopolymer. These peptides appear to inhibit metabolic processes, such as protein synthesis or chaperone-assisted protein folding. Pyrrhocoricin derivatives protect mice from experimental infections in vivo, suggesting the utility of modified analogs in the clinical setting. Sequence variations of the target protein at the peptide-binding site may allow the development of new peptide variants that kill currently unresponsive strains or species. Received 12 December 2001; received after revision 11 February 2002; accepted 19 February 2002     

生物活性环二肽研究进展

在对近年来活性环二肽的发现及其合成策略进行了综述的基础上,指出环二肽在自然界及天然产物中广泛存在,由于其结构特殊,使得环二肽成为药物化学中一个重要的药效团,许多环二肽具有强的生理活性．     

GPCR配体药效团数据库的构建

G蛋白偶联受体(GPCR)是人体内一类重要的药物作用靶标.针对GPCR配体进行了较全面的药效团模拟研究,有效地整合针对GPCR进行药物发现研究的数据,并构建了相应的药效团数据库.收集并构建了GPCR的8个大类17个亚型的不同配体共110个药效团模型,作为GPCR配体药效团数据库的首批数据.通过统计分析发现:87%GPCR配体药效团中含有疏水性基团(Hydrophobic,HY),66%包含芳香性基团(Ring aromatic,RA),45%含有正离子基团(Positive ions,PI),GPCR药效团数据库的建立极大地方便了开发设计新的具有选择性的GPCR配体.