Kawai Akito, Kobashigawa Yoshihiro, Hirata Kenshiro, Morioka Hiroshi, Imoto Shuhei, Nishi Koji, Chuang Victor Tuan Giam, Yamasaki Keishi, Otagiri Masaki
Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi 5-1, Chuo-ku, Kumamoto 862-0973, Japan.
ACS Omega. 2022 Aug 18;7(34):29944-29951. doi: 10.1021/acsomega.2c02929. eCollection 2022 Aug 30.
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.
阿立哌唑（ARP）是一种抗精神病药物，与其他ARP衍生物相比，它与人血清白蛋白（HSA）的结合更强。此外，与ARP或去氯ARP复合的HSA的外在科顿效应的符号是相反的。在本研究中，我们报告了一种使用圆二色性（CD）光谱分析、X射线晶体学分析和分子动力学模拟的结构化学方法。目的是研究诱导CD光谱与HSA与ARP或去氯ARP复合物的结构特征之间的关系。随着温度升高，HSA与ARP或去氯ARP复合物的诱导CD光谱强度降低。我们在本研究中确定了与去氯ARP复合的HSA的晶体结构，并将其与我们之前报道的与ARP复合的HSA进行了比较。这些结构的比较表明，ARP和去氯ARP都结合在HSA的位点II口袋中，并且分子的取向几乎相同。分子动力学模拟表明，ARP和去氯ARP在位点II口袋内的分子运动彼此不同，并且Tyr411与ARP和去氯ARP的二氢喹啉环的堆积相互作用形成比例也不同。这些发现表明，诱导CD光谱与ARP和去氯ARP在HSA中的分子运动和动态相互作用有关，并且可能有助于更清楚地理解其他HSA配体结合位点内发生的分子识别和运动。
