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

Kenshiro Hirata, Akito Kawai, Victor Tuan Giam Chuang, Keiki Sakurama, Koji Nishi, Keishi Yamasaki, Masaki Otagiri

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Abstract

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.

Original languageEnglish
Pages (from-to)4413-4419
Number of pages7
JournalACS Omega
Volume7
Issue number5
DOIs
Publication statusPublished - 08-02-2022

All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

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