کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
2486962 | 1114398 | 2009 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
A Site-Directed Mutagenesis Study of Drug-Binding Selectivity in Genetic Variants of Human α1-Acid Glycoprotein
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کلمات کلیدی
موضوعات مرتبط
علوم پزشکی و سلامت
داروسازی، سم شناسی و علوم دارویی
اکتشاف دارویی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Human α1-acid glycoprotein (AGP), a major carrier of many basic drugs in circulation, consists of at least two genetic variants, namely A and F1*S variant. Interestingly, the variants of AGP have different drug-binding properties. The purpose of this study was to identify the amino acid residues that are responsible for the selectivity of drug binding to genetic variants of AGP using site-directed mutagenesis. First, we screened amino acid residues in the region proximal to position 100 that are involved in binding of warfarin and dipyridamole, which are F1*S-specific ligands, and of propafenone, which is an A-specific ligand, using ultrafiltration. In the F1*S variant, His97, His100, and Trp122 were involved in either warfarin- or dipyridamole-binding, while Glu92, His100, and Trp122 participated in the binding of propafenone in the A variant. Exchange of the residue at position 92 between AGP variants reversed the relative strength of propafenone binding to the two variants, but had a markedly different effect on binding of warfarin and dipyridamole. These findings indicate that the amino acid residue at position 92 plays a significant role in drug-binding selectivity in AGP variants, especially for drugs that preferentially bind to the A variant. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:4316-4326, 2009
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Journal of Pharmaceutical Sciences - Volume 98, Issue 11, November 2009, Pages 4316-4326
Journal: Journal of Pharmaceutical Sciences - Volume 98, Issue 11, November 2009, Pages 4316-4326
نویسندگان
Koji Nishi, Megumi Ueno, Yuka Murakami, Naoko Fukunaga, Teruo Akuta, Daisuke Kadowaki, Hiroshi Watanabe, Ayaka Suenaga, Toru Maruyama, Masaki Otagiri,