人类和犬类P-糖蛋白基质在R,P和H结合位点的比较
Neal S Burke1, Katrina L Mealey1
1Program in Individualized Medicine (PrIMe), College of Veterinary Medicine, Washington State University, Pullman, Washington, USA.
Journal of veterinary pharmacology and therapeutics
|November 19, 2025
概括
人类P-glycoprotein (P-gp) 药物数据经常不准确地预测狗P-gp基质状态. 了解P-gp结合部位对于准确的犬类药物处置评估至关重要.
科学领域:
- 药理学 药理学是指药理学的学科.
- 生物化学 生化学
- 兽医医学 兽医医学 兽医医学
背景情况:
- P-glycoprotein (P-gp) 显著影响人类的药物处置,需要对活性药物成分 (API) 进行监管评估.
- 评估P-gp基质状态对于犬类药物开发也至关重要,但人类数据可能无法可靠地翻译.
- P-gp结合口袋包含三个不同的位点 (H,R和P),影响基质相互作用.
研究的目的:
- 为了确定人类P-gp基质数据是否可以预测犬类P-gp基质状态.
- 研究犬类与人类P-gp中的H,R和P结合位的作用和重叠.
主要方法:
- 竞争性排泄试验是使用被设计成表达犬类或人类P-gp的细胞系进行的.
- 使用特定位点的光基质 (罗达胺123,素AM,霍希斯特33342) 来比较结合位点的相互作用.
- 进行了实验,以排除多重耐药性相关蛋白1 (MRP1) 对素AM流量的影响.
主要成果:
- 多种药物耐药性相关蛋白1 (MRP1) 在狗或人类细胞系的P-gp流量研究中没有显著影响.
- 对P-gp结合部位的分析揭示了犬类和人类P-gp之间的明显相互作用模式.
- 人类P-gp基质数据经常无法准确预测犬类P-gp基质状态.
结论:
- 人类P-gp基质数据通常不可靠,无法预测犬类P-gp基质状态.
- 对API的特定P-gp结合位相互作用的描述可以为兽医药提供临床相关的见解.
- 对犬类P-gp结合特异性的进一步研究是有必要的,以改善狗类药物开发.
相关概念视频
Ligand Binding and Linkage
5.4K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
5.4K
Protein-Drug Binding: Mechanism and Kinetics
1.6K
Protein-drug binding refers to the interaction between drugs and proteins within the body. This binding process can occur intracellularly, involving drug interactions with enzymes or receptors within cells, or extracellularly, involving plasma proteins in the blood.
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
Various forces drive these interactions, including hydrogen bonds, hydrophobic interactions, ionic bonds, electrostatic interactions, and van der Waals forces. These bonds enable drugs to bind to specific sites on proteins,...
1.6K
Protein-Drug Binding: Determination Methods
603
Determining protein-drug binding can be achieved through indirect and direct methods, each providing valuable insights into the interaction between proteins and drugs.
Indirect methods involve isolating the bound drug from its free form in biological samples such as blood, serum, or plasma. These techniques aim to measure the percentage of drugs bound to proteins. Equilibrium dialysis is a commonly used method where the free drug concentration at equilibrium is measured by separating the bound...
Indirect methods involve isolating the bound drug from its free form in biological samples such as blood, serum, or plasma. These techniques aim to measure the percentage of drugs bound to proteins. Equilibrium dialysis is a commonly used method where the free drug concentration at equilibrium is measured by separating the bound...
603
Allosteric Proteins-ATCase
6.4K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
6.4K
Ligand Binding Sites
14.8K
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...
14.8K
Protein-protein Interfaces
14.4K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
14.4K


