赖氨酸
人血清白蛋白
化学
半胱氨酸
酪氨酸
谷胱甘肽
生物化学
布鲁顿酪氨酸激酶
体内
共价键
肽
生物利用度
血浆蛋白结合
药品
白蛋白
体外
氨基酸
药理学
酪氨酸激酶
酶
生物
受体
有机化学
生物技术
作者
Cathy Muste,Chungang Gu
标识
DOI:10.1016/j.dmpk.2021.100433
摘要
Irreversible Bruton's tyrosine kinase (BTK) inhibitor drugs are designed to bind covalently to a free-thiol cysteine in the BTK protein active site. However, these reactive drugs bind to off-target proteins as well. In this study, seven BTK-inhibitor drugs containing acrylamide warheads were incubated with human serum albumin (HSA) and analyzed using an LC-MS/MS peptide mapping approach to determine the amino acid sites of drug covalent binding. Significant adduction at the free-thiol cysteine of HSA was only observed for two of the drugs. However, significant adduction was observed for at least four lysine residues. This is just a small percentage of the 59 total lysine residues in HSA. These four lysine residues are likely partially buried, accessible to the drugs, and exist at least partially in a neutral state. The levels of adduction observed in the in-vitro experimental conditions are only indicative of a relative propensity for adduction with the individual lysine residues of HSA, and are not in-vivo predictions. Widespread off-target lysine binding could impact clearance and bioavailability for irreversible inhibitor drugs. However, the extent of the impact on clearance may be limited in comparison to conjugation with glutathione.
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