An overview of albumin and alpha-1-acid glycoprotein main characteristics: highlighting the roles of amino acids in binding kinetics and molecular interactions

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Abstract

Although Albumin (ALB) and alpha-1-acid glycoprotein (AGP) have distinctive structural and functional characteristics, they both play a key role in binding a large variety of endogenous and exogenous ligands.

An extensive binding to these plasma proteins could have a potential impact on drugs disposition (e.g. bioavailability, distribution and clearance), on their innocuity and their efficacy. This review summarizes the common knowledge about the structural and molecular characteristics of both ALB and AGP in humans, and about the most involved amino acids in their high-affinity binding pockets. However, the variability in residues found in binding pockets, for the same species, allows each plasma protein to interact differently with the ligands. The protein-ligand interaction influences differently the disposition of drugs that bind to either of these plasma proteins.

The content of this review is useful for the design of new drug entities with high-binding characteristics, in qualitative and quantitative modelling (e.g. in vitro-in vivo extrapolations, 3D molecular docking, interspecies extrapolations), and for other interdisciplinary research.

Abstract

Plasma protein binding; Protein-ligand complex; Albumin; Alpha-1-acid glycoprotein; Molecular interactions

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Atomic structure and chemistry of human serum albumin.

X. M. He, D. Carter (1992)

The three-dimensional structure of human serum albumin has been determined crystallographically to a resolution of 2.8 A. It comprises three homologous domains that assemble to form a heart-shaped molecule. Each domain is a product of two subdomains that possess common structural motifs. The principal regions of ligand binding to human serum albumin are located in hydrophobic cavities in subdomains IIA and IIIA, which exhibit similar chemistry. The structure explains numerous physical phenomena and should provide insight into future pharmacokinetic and genetically engineered therapeutic applications of serum albumin.

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Structural basis of the drug-binding specificity of human serum albumin.

Jamie Ghuman, Patricia A Zunszain, Isabelle Petitpas … (2005)

Human serum albumin (HSA) is an abundant plasma protein that binds a remarkably wide range of drugs, thereby restricting their free, active concentrations. The problem of overcoming the binding affinity of lead compounds for HSA represents a major challenge in drug development. Crystallographic analysis of 17 different complexes of HSA with a wide variety of drugs and small-molecule toxins reveals the precise architecture of the two primary drug-binding sites on the protein, identifying residues that are key determinants of binding specificity and illuminating the capacity of both pockets for flexible accommodation. Numerous secondary binding sites for drugs distributed across the protein have also been identified. The binding of fatty acids, the primary physiological ligand for the protein, is shown to alter the polarity and increase the volume of drug site 1. These results clarify the interpretation of accumulated drug binding data and provide a valuable template for design efforts to modulate the interaction with HSA.