6a7p
Human serum albumin complexed with aripiprazole
Structural highlights
DiseaseALBU_HUMAN Defects in ALB are a cause of familial dysalbuminemic hyperthyroxinemia (FDH) [MIM:103600. FDH is a form of euthyroid hyperthyroxinemia that is due to increased affinity of ALB for T(4). It is the most common cause of inherited euthyroid hyperthyroxinemia in Caucasian population.[1] [2] [3] [4] FunctionALBU_HUMAN Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloidal osmotic pressure of blood. Major zinc transporter in plasma, typically binds about 80% of all plasma zinc.[5] Publication Abstract from PubMedAripiprazole (ARP), a quinolinone derivative, is an atypical antipsychotic drug that is used in the treatment of schizophrenia. ARP has an extensive distribution and more than 99% of the ARP and dehydro-ARP, the main active metabolite, is bound to plasma proteins. However, information regarding the protein binding of ARP is limited. In this study, we report on a systematic study of the protein binding of ARP. The interaction of ARP and structurally related compounds with human serum albumin (HSA) was examined using equilibrium dialysis, circular dichroism (CD) spectroscopy, fluorescent probe displacement, and an X-ray crystallographic analysis. The binding affinities (nK) for ARP and its main metabolite, dehydro-ARP with HSA were found to be significantly higher than other structurally related compounds. The results of equilibrium dialysis experiments and CD spectral data indicated that the chloro-group linked to the phenylpiperazine ring in the ARP molecule plays a major role in the binding of these ligands to HSA. Furthermore, fluorescent probe displacement results indicated that ARP appears to bind at the site II pocket in subdomain III. A detailed CD spectral analysis suggests that the chloro-group linked to the phenylpiperazine ring may control the geometry of the ARP molecule when binding in the site II binding pocket. X-ray crystallographic analysis of the ARP-HSA complex revealed that the distance between the chlorine atom at the 3-positon of dichlorophenyl-piperazine on ARP and the sulfur atom of Cys392 in HSA was 3.4-3.6 A. A similar halogen bond interaction has also been observed in the HSA structure complexed with diazepam, which also contains a chloro-group. Thus, the mechanism responsible for the binding of ARP to a protein elucidated here should be relevant for assessing the pharmacokinetics and pharmacodynamics of ARP in various clinical situations and for designing new drugs. Analysis of the Binding of Aripiprazole to Human Serum Albumin: The Importance of a Chloro-Group in the Chemical Structure.,Sakurama K, Kawai A, Tuan Giam Chuang V, Kanamori Y, Osa M, Taguchi K, Seo H, Maruyama T, Imoto S, Yamasaki K, Otagiri M ACS Omega. 2018 Oct 31;3(10):13790-13797. doi: 10.1021/acsomega.8b02057. Epub, 2018 Oct 22. PMID:30411049[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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