多様なリガンドのための仮想スクリーン:選択的なGタンパク質結合受容体対抗体の発見
Stanislav Engel1, Amanda P Skoumbourdis, John Childress
1The Clinical Endocrinology Branch and Laboratory of Biological Modeling, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Journal of the American Chemical Society
|March 25, 2008
まとめ
新しい仮想スクリーニング方法は,Gタンパク質結合受容体 (GPCR) 薬剤発見における課題を克服しています. このアプローチにより,タイロトロピン放出ホルモン受容体 (TRH-R1およびTRH-R2) の新しい抗体が見つかりました.
科学分野:
- バイオケミストリー バイオケミストリー
- 薬理学 薬理学とは
- コンピューティング・ケミストリー
背景:
- 仮想スクリーニングは,生物活性小分子を特定するための鍵ですが,Gタンパク質結合受容体 (GPCRs) との成功は限られています.
- GPCRは,構造データの不足と固有の柔軟性のために課題を提示し,受容体ベースの仮想スクリーニングを複雑にします.
- 既存の方法は,GPCRにおける構造的不確実性と柔軟性を説明するのに苦労しています.
研究 の 目的:
- 構造的不確実性に対処するGPCRをターゲットとした仮想スクリーニングのための in silico方法論を開発し,検証する.
- タイロトロピンを放出するホルモン受容体 (TRH-R1とTRH-R2) の新しい小分子アンタゴニストを特定する.
主な方法:
- GPCRsの仮想スクリーニングにおける構造的不確実性を軽減するために,新しい in silico 方法論を開発しました.
- 開発された方法論を使用して,仮想データベースから100万の化合物をスクリーニングしました.
- TRH受容体の変異分析を含む実験的検証のために100の多様な化合物を選択しました.
主要な成果:
- タイロトロピン放出ホルモン受容体 (TRH-R1とTRH-R2) の5つの構造的に異なったアンタゴニストを特定しました.
- キラリティは結合親和性において決定的であり,あるステレオイソメアはTRH-R1に対してTRH-R2.0よりも13倍の選択性を示した.
- 変異分析は,特定された小分子抗生物質の結合方法を確認しました.
結論:
- この新しい仮想スクリーニングアプローチは,構造的な課題にもかかわらず,GPCRアンタゴニストを効果的に特定します.
- この方法論は,他のGPCRターゲットの新規アゴニストおよびアンタゴニストの発見に有望である.
- この発見は,TRH受容体の抗体設計におけるキラリティの重要性を強調しています.
関連する概念動画
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
G Protein-coupled Receptors
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
G-protein Coupled Receptors
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
Ligand Binding Sites
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Ligand Binding Sites
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...


