共查询到18条相似文献,搜索用时 93 毫秒
1.
G蛋白偶联受体(GPCR)是受体中家族成员最多的一大类,其活性涉及体内绝大部分的生理功能,在药物研发过程中是主要的药物作用靶标。研究表明,GPCR及其突变体在缺乏配体结合的情况下,能自发地产生一定程度的内在活性,即GPCR的组成性活性(constitutive activity);其相应的反向激动剂与GPCR结合能降低受体的组成性活性,在药物治疗学上具有重要意义。愈来愈多的实验表明,GPCR组成性活性及反向激动剂的研究具有广阔和实际的应用前景,对其进行深入研究在受体学说领域和药物研发过程中具有重要理论意义。 相似文献
2.
3.
4.
5.
针对G蛋白偶联受体的药物筛选新方法 总被引:1,自引:0,他引:1
G蛋白偶联受体(GPCR)为具有7个跨膜螺旋的蛋白质受体,是人体内最大的蛋白质家族,其为极重要的药物靶点。本文针对GPCR的固有激活和变构效应的药物筛选模型开发新进展和高内涵药物筛选新技术进行综述。 相似文献
6.
7.
8.
9.
10.
11.
Chen G Way J Armour S Watson C Queen K Jayawickreme CK Chen WJ Kenakin T 《Molecular pharmacology》2000,57(1):125-134
This article describes the behavior of transiently transfected human receptors into melanophores and the potential use of constitutive receptor activity to screen for new drug entities. Specifically, transient transfection of melanophores with different concentrations of receptor cDNA presumably leads to increased levels of receptor expression. This leads to an increased response to agonists (both maxima and potency) and, in some cases, an agonist-independent constitutive receptor activity. Transfections with increasing concentrations of the G(s) protein-coupled human calcitonin receptor type 2 (hCTR2) cDNA produced sufficient levels of constitutively activated receptor to cause elevated basal cellular responses. This was observed as a decrease in the transmittance of light through melanophores (consistent with G(s) protein activation) and increased response to human calcitonin. The receptor-mediated nature of this response was confirmed by its reversal with the hCTR2 peptide inverse agonist AC512. A collection of ligands for hCTR2 either increased or decreased constitutive hCTR2 activity, suggesting that the constitutive system was a sensitive discriminator of positive and negative ligand efficacy. Similar results were obtained with G(i)-protein-coupled receptors. Transient transfection of NPY1, NPY2, NPY4, CXCR4, and CCR5 cDNA produced increased light transmittance through melanophores (consistent with G(i)-protein activation). NPY1 cDNA produced little constitutive response on transfection, whereas maximal levels of constitutive activity ranging from 30 to 45% were observed for the other G(i)-protein-coupled receptors. Responses to agonists for these receptors increased (both maxima and potency) with increasing cDNA transfection. The receptor/G(i)-protein nature of both the constitutive and agonist-mediated responses was confirmed by elimination with pertussis toxin pretreatment. These data are discussed in terms of the theoretical aspects of constitutive receptor activity and the applicability of this approach for the general screening of G protein-coupled orphan receptors. 相似文献
12.
G protein-coupled receptors (GPCRs) represent one of the most important drug discovery targets such that compounds targeted against GPCRs represent the single largest drug class currently on the market. With the revolutionary advances in human genome sciences and the identification of numerous orphan GPCRs, it is even more important to identify ligands for these orphan GPCRs so that their physiological and pathological roles can be delineated. To this end, major pharmaceutical industries are investing enormous amounts of time and money to achieve this object. This review is a bird's eye view on the various aspects of GPCRs in drug discovery. 相似文献
13.
《Drug discovery today》2015,20(11):1355-1364
- Download : Download high-res image (244KB)
- Download : Download full-size image
14.
G protein-coupled receptors (GPCRs) are the key elements of a highly regulated transduction machinery that generates different signaling outcomes to hormones and neurotransmitters. Until recently, it was assumed that diverse ligands of a given GPCR differ only in their ability to alter the balance between the OFF and the ON state of the receptor. However, it has now become evident that their activation mechanisms are more complex and that receptors presumably display distinguishable active conformational states, which are induced by different agonists and correlate to specific signaling outputs. The use of different labeling strategies to insert fluorescent labels into purified, reconstituted receptors, or into receptors in intact cells, has made it possible to sense receptor activation via changes in their fluorescence. Here, we summarize recent progress in the analysis of agonist-dependent activation mechanisms of GPCRs acquired using modern spectroscopic and crystallographic techniques. 相似文献
15.
《Expert opinion on drug discovery》2013,8(2):137-150
Steroid-binding receptors have long been a successful target class for the pharmaceutical industry. Clinical applications for steroids range from contraception and hormone replacement therapy to immune regulation and cancer therapy. With the recent demonstration that the orphan GPCR, GPR30 binds and is activated by estrogen, as well as the identification of a GPR30-selective agonist, it is likely that GPR30 represents a novel drug target with many potential clinical applications. This review discusses the role of GPR30 in mediating the effects of estrogen, as well as recent efforts to isolate GPR30-specific ligands using a combination of virtual and biomolecular screening. Finally, comments are made on the future directions regarding GPCRs, steroids and drug discovery. 相似文献
16.
G蛋白偶联受体(GPCRs)是与G蛋白相偶联的七次跨膜受体,其成员有上千种,是重要的药物靶点之一。目前,GPCRs相关药物占市场上药物的40%-50%。在过去的十年中,对GPCRs主要以单体的形式存在着的这一假说做出了重新评估,大量事实证明GPCRs也能以同源或异源二聚体,甚至是高阶寡聚体的形式存在,比较热门的领域是GPCRs二聚化。最近研究表明同源或异源二聚化有不同于单体的特异功能特征,包括配体识别、信号转导、运输等。同时,在较少副作用治疗疾病的新药开发上,具有不同病理和信号转导途径的二聚体的出现开辟了新的领域。本综述主要介绍二聚体的特异结构及其特异的信号转导途径,从而有助于在GPCRs药物开发中取得丰硕的成果。 相似文献
17.
18.
G protein-coupled receptors (GPCRs) are the largest family of membrane-bound receptors and also the targets of many drugs. Understanding of the functional significance of the wide structural diversity of GPCRs has been aided considerably in recent years by the sequencing of the human genome and by structural studies, and has important implications for the future therapeutic potential of targeting this receptor family. This article aims to provide a comprehensive overview of the five main human GPCR families--Rhodopsin, Secretin, Adhesion, Glutamate and Frizzled/Taste2--with a focus on gene repertoire, general ligand preference, common and unique structural features, and the potential for future drug discovery. 相似文献