Interaction of Aripiprazole With Human α1-Acid Glycoprotein

Nishi, Koji; Sakurama, Keiki; Kobashigawa, Yoshihiro; Morioka, Hiroshi; Udo, Nagiko; Hashimoto, Michihiro; Imoto, Shuhei; Yamasaki, Keishi; Otagiri, Masaki

doi:10.1016/j.xphs.2019.09.003

Cited by 6 publications

(10 citation statements)

References 22 publications

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“…This construct incorporated a cleavable N-terminal His6-tag and the C149R mutation shown to improve solution homogeneity of deglycosylated forms used in crystallographic studies (14). We employed a rapid dilution refolding strategy to form the two disulphide bridges (Cys 5 -Cys 147 and Cys 72 -Cys 165) as opposed to cytoplasmic folding methods (26). After refolding and removal of the N-terminal His6-tag, analytical size exclusion chromatography indicated the presence of a ~ 22 kDa species (Supporting Information Figure 1) consistent with monomeric, non-glycosylated protein with no indication of aggregation.…”

Section: Resultsmentioning

confidence: 99%

The structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01

Landin

Williams

Ryan

et al. 2021

Journal of Biological Chemistry

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The α1-acid glycoprotein (AGP) is an abundant blood plasma protein with important immunomodulatory functions coupled to endogenous and exogenous ligand-binding properties. Its affinity for many drug-like structures, however, means AGP can have a significant effect on the pharmokinetics and pharmacodynamics of numerous small molecule therapeutics. Staurosporine, and its hydroxylated forms UCN-01 and UCN-02, are kinase inhibitors that have been investigated at length as antitumour compounds. Despite their potency, these compounds display poor pharmokinetics due to binding to both AGP variants, AGP1 and AGP2. The recent renewed interest in UCN-01 as a cytostatic protective agent prompted us to solve the structure of the AGP2–UCN-01 complex by X-ray crystallography, revealing for the first time the precise binding mode of UCN-01. The solution NMR suggests AGP2 undergoes a significant conformational change upon ligand binding, but also that it uses a common set of sidechains with which it captures key groups of UCN-01 and other small molecule ligands. We anticipate that this structure and the supporting NMR data will facilitate rational redesign of small molecules that could evade AGP and therefore improve tissue distribution.

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Section: Resultsmentioning

confidence: 99%

The structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01

Landin

Williams

Ryan

et al. 2021

Journal of Biological Chemistry

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“…Examples of recent studies on drugs bound by AGP include: Warfarin ( Hanada, 2017 ), Pinometostat ( Smith et al, 2017 ), Aripiprazole ( Nishi et al, 2019 ), Imatinib ( Mic et al, 2020 ), Voriconazole ( Yuan et al, 2020 ), ONO-2160 ( Kono et al, 2019 , 2021 ), SCO-272 ( Ebihara et al, 2018 , 2019 ), and Brigatinib ( Wang et al, 2020 ).…”

Section: Agp Ligands and Receptorsmentioning

confidence: 99%

Into the Labyrinth of the Lipocalin α1-Acid Glycoprotein

Ruiz

2021

Front. Physiol.

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α1-acid glycoprotein (AGP), also known as Orosomucoid (ORM), belongs to the Lipocalin protein family and it is well-known for being a positive acute-phase protein. AGP is mostly found in plasma, with the liver as main contributor, but it is also expressed in other tissues such as the brain or the adipose tissue. Despite the vast literature on AGP, the physiological functions of the protein remain to be elucidated. A large number of activities mostly related to protection and immune system modulation have been described. Recently created AGP-knockout models have suggested novel physiological roles of AGP, including regulation of metabolism. AGP has an outstanding ability to efficiently bind endogenous and exogenous small molecules that together with the complex and variable glycosylation patterns, determine AGP functions. This review summarizes and discusses the recent findings on AGP structure (including glycans), ligand-binding ability, regulation, and physiological functions of AGP. Moreover, this review explores possible molecular and functional connections between AGP and other members of the Lipocalin protein family.

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“…In addition, the heat capacity for the interaction of ARP with HSA was significantly greater than that for the deschloro-ARP–HSA system. 7 These differences in interaction between ARP and deschloro-ARP and HSA led us to hypothesize that the interaction mode of these two ligands with HSA could be different. Thus, in our continuous investigations, we examined the binding geometry of ARP and deschloro-ARP within the binding pocket of HSA using structural–chemical approaches including CD spectroscopic analysis, X-ray crystallographic analysis, and molecular dynamics (MD) simulations.…”

Section: Introductionmentioning

confidence: 99%

Chlorine Atoms of an Aripiprazole Molecule Control the Geometry and Motion of Aripiprazole and Deschloro-aripiprazole in Subdomain IIIA of Human Serum Albumin

et al. 2022

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Aripiprazole (ARP), an antipsychotic drug, binds more strongly to human serum albumin (HSA) than the other ARP derivatives. In addition, the signs for the extrinsic Cotton effects for HSA complexed with ARP or deschloro-ARP are reversed. In this study, we report on a structural–chemical approach using circular dichroism (CD) spectroscopic analysis, X-ray crystallographic analysis, and molecular dynamics simulations. The objective was to examine the relationship between the induced CD spectra and the structural features of the HSA complexes with ARP or deschloro-ARP. The intensity of the induced CD spectra of the HSA complexes with ARP or deschloro-ARP was reduced with increasing temperature. We determined the crystal structure of the HSA complexed with deschloro-ARP in this study and compared it to HSA complexed with ARP that we reported previously. The comparison of these structures revealed that both ARP and deschloro-ARP were bound at the site II pocket in HSA and that the orientation of the molecules was nearly identical. Molecular dynamics simulations indicated that the molecular motions of ARP and deschloro-ARP within the site II pocket were different from one another and the proportion of stacking interaction formations of Tyr411 with the dihydroquinoline rings of ARP and deschloro-ARP was also different. These findings indicate that the induced CD spectra are related to the molecular motions and dynamic interactions of ARP and deschloro-ARP in HSA and may help to understand the molecular recognition and motion that occurs within the binding site for the other HSA ligands more clearly.

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Interaction of Aripiprazole With Human α1-Acid Glycoprotein

Cited by 6 publications

References 22 publications

The structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01

The structural basis for high affinity binding of α1-acid glycoprotein to the potent antitumor compound UCN-01

Into the Labyrinth of the Lipocalin α1-Acid Glycoprotein

Chlorine Atoms of an Aripiprazole Molecule Control the Geometry and Motion of Aripiprazole and Deschloro-aripiprazole in Subdomain IIIA of Human Serum Albumin

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