Further Evidence Regarding the Important Role of Chlorine Atoms of Aripiprazole on Binding to the Site II Area of Human Albumin

Sakurama, Keiki; Nishi, Koji; Imoto, Shuhei; Hashimoto, Michihiro; Komatsu, Teruyuki; Morita, Yoshitsugu; Taguchi, Kazuaki; Otagiri, Masaki; Yamasaki, Keishi

doi:10.1016/j.xphs.2018.11.045

Cited by 6 publications

(5 citation statements)

References 20 publications

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“…We recently reported on the binding parameters of aripiprazole (ARP), a quinolinone derivative and atypical antipsychotic drugs, to HSA. , An extrinsic positive Cotton effect for ARP bound to HSA was observed at around 265 nm, and a negative Cotton effect was observed at about 300 nm. In addition, we found that myristate caused the reversal of the induced Cotton effects of ARP–HSA.…”

Section: Introductionsupporting

confidence: 88%

Effects of Myristate on the Induced Circular Dichroism Spectra of Aripiprazole Bound to Human Serum Albumin: A Structural–Chemical Investigation

et al. 2022

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The effects of myristate on the induced circular dichroism spectra of aripiprazole (ARP) bound to human serum albumin (HSA) were investigated. High concentrations of myristate reversed the Cotton effects induced in the ARP–HSA system. The observed ellipticities increased with increasing drug concentration up to an ARP-to-HSA molar ratio of 1:1 and then decreased, indicating that the extrinsic Cotton effects were generated by the binding of ARP molecules to the high- and low-affinity sites in HSA. The data for the concentration of free ARP show that myristate displaces ARP molecules from HSA. Moreover, the free fractions of ARP in the ARP–HSA–myristate system increased significantly when adding fusidic acid, a subdomain IB ligand. In the crystal structure of the ARP–HSA–myristate ternary complex, one ARP molecule is bound to subdomain IB, and the interaction between the carbonyl group of ARP and the aromatic ring of Tyr138 in subdomain IB is essential for binding to occur. Meanwhile, the ARP molecule in the ARP–HSA binary complex structure is bound only to subdomain IIIA. Consequently, the inversion in the extrinsic Cotton effects in the ARP–HSA system can be attributed to the modification of the geometry within the binding pocket, in addition to the transfer of ARP from subdomain IIIA to subdomain IB through the displacement as a result of the binding of myristate to subdomain IIIA.

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Section: Introductionsupporting

confidence: 88%

Effects of Myristate on the Induced Circular Dichroism Spectra of Aripiprazole Bound to Human Serum Albumin: A Structural–Chemical Investigation

et al. 2022

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“…Equilibrium Dialysis Equilibrium dialysis was performed using Sanko plastic dialysis cells (Fukuoka, Japan) at 25þC for 12 h. According to our previous method, 8) same volume of the buffer and ARP-HSA mixture solutions were set to each compartment, respectively. After dialysis, the concentrations of ARP in the buffer (Df, free ARP concentration) and HSA compartments (Dt, total concentrations of ligand) were measured by HPLC.…”

Section: Methodsmentioning

confidence: 99%

“…We recently reported that aripiprazole (ARP), an antipsychotic drug, shows high affinity binding to HSA. 8,9) An X-ray crystallographic study showed that the chlorine atom of ARP interacted with cysteine (Cys) residue at position 34 in HSA, similar to diazepam-HSA interactions. 10) Very recently, we reported the decreased binding affinity of ARP to chemically oxidized HSA as a model of HSA observed in the patients with chronic renal failure, 11) and indicated a significantly lower binding ability for oxidized HSA, compared to normal HSA.…”

Section: Introductionmentioning

confidence: 99%

Effects of Uremic Toxins on the Binding of Aripiprazole to Human Serum Albumin

Nishi

Sakurama

Watanabe

et al. 2021

Biological & Pharmaceutical Bulletin

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We recently reported that aripiprazole (ARP), an antipsychotic drug, binds strongly to human serum albumin (HSA), the major drug binding protein in serum. It is known that uremic toxins that accumulate during renal disease affect the interaction between HSA and drug binding. In this study, the issue of how uremic toxins (indoxyl sulfate, indole acetic acid and p-cresyl sulfate) affect the binding of ARP to HSA was investigated. Equilibrium dialysis experiments revealed that all uremic toxins inhibited the binding of ARP to HSA although the inhibitory effects differed, depending on the specific uremic toxin. The potency of inhibition can be partially explained by the affinities of uremic toxins to HSA. Fluorescence displacement experiments suggested that ARP as well as all uremic toxins bind to site II of HSA. The inhibitory effects of the toxins on the binding of ARP for the drugs binding to the diazepam subsite are significantly larger, comparing with those for binding to arylpropionic acids subsite. Interestingly, induced circular dichroism (CD) spectra indicated that the spatial orientation of p-cresyl sulfate in the binding pocket is different from that for indoxyl sulfate and indole acetic acid. The limited findings obtained herein are important data in considering the effects of uremic toxins on the pharmacokinetics of ARP and the drugs that bind to site II on HSA, particularly drugs binding to diazepam binding site in site II.

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“…We previously reported that the induced CD spectra were observed in the HSA complexes with ARP and its derivatives and that only the deschloro-ARP−HSA complex showed an extrinsic Cotton effect at 265 nm with a reversed sign. 5,6 This reversal in the sign of the extrinsic Cotton effect appears to depend on differences in the structures of ARP and its derivatives, particularly in the presence of chlorine atoms. In this study, we further examined the temperature dependency of the extrinsic Cotton effects generated from the interaction of ARP and deschloro-ARP with HSA.…”

Section: Temperature Dependency Of Extrinsic Cotton Effects For the H...mentioning

confidence: 98%

“…We recently studied the binding properties of ARP derivatives to plasma proteins as part of a preliminary pharmacokinetic evaluation of these molecules. ARP binds to human serum albumin (HSA) and the α 1 -acid glycoprotein. − ARP binds more strongly to HSA than the other ARP derivatives, and the binding affinity of ARP to HSA (5.94 × 10 6 M –1 ) is more than 50 times higher than that of deschloro-ARP (0.10 × 10 6 M –1 ) . We determined the crystal structure of HSA complexed with ARP, and the results indicated that the binding position of ARP overlaps with the fatty acid binding sites 3 and 4 in HSA .…”

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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Further Evidence Regarding the Important Role of Chlorine Atoms of Aripiprazole on Binding to the Site II Area of Human Albumin

Cited by 6 publications

References 20 publications

Effects of Myristate on the Induced Circular Dichroism Spectra of Aripiprazole Bound to Human Serum Albumin: A Structural–Chemical Investigation

Effects of Myristate on the Induced Circular Dichroism Spectra of Aripiprazole Bound to Human Serum Albumin: A Structural–Chemical Investigation

Effects of Uremic Toxins on the Binding of Aripiprazole to Human Serum Albumin

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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