Analysis of the Binding of Aripiprazole to Human Serum Albumin:The Importance of a Chloro-Group in the Chemical Structure

摘要

Aripiprazole (ARP), a quinolinone derivative,is an atypical antipsychotic drug that is used in the treatmentof schizophrenia. ARP has an extensive distribution and morethan 99% of the ARP and dehydro-ARP, the main activemetabolite, is bound to plasma proteins. However, information regarding the protein binding of ARP is limited. In thisstudy, we report on a systematic study of the protein bindingof ARP. The interaction of ARP and structurally relatedcompounds with human serum albumin (HSA) was examinedusing equilibrium dialysis, circular dichroism (CD) spectroscopy, fluorescent probe displacement, and an X-ray crystallographic analysis. The binding affinities (nK) for ARP and itsmain metabolite, dehydro-ARP with HSA were found to besignificantly higher than other structurally related compounds. The results of equilibrium dialysis experiments and CD spectraldata indicated that the chloro-group linked to the phenylpiperazine ring in the ARP molecule plays a major role in the bindingof these ligands to HSA. Furthermore, fluorescent probe displacement results indicated that ARP appears to bind at the site IIpocket in subdomain III. A detailed CD spectral analysis suggests that the chloro-group linked to the phenylpiperazine ring maycontrol the geometry of the ARP molecule when binding in the site II binding pocket. X-ray crystallographic analysis of theARP?HSA complex revealed that the distance between the chlorine atom at the 3-positon of dichlorophenyl-piperazine on ARPand the sulfur atom of Cys392 in HSA was 3.4?3.6 ?. A similar halogen bond interaction has also been observed in the HSAstructure complexed with diazepam, which also contains a chloro-group. Thus, the mechanism responsible for the binding ofARP to a protein elucidated here should be relevant for assessing the pharmacokinetics and pharmacodynamics of ARP invarious clinical situations and for designing new drugs.