Mass spectrometry methods and mathematical PK/PD model for decision tree-guided covalent drug development.

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Tác giả: Jeffrey N Agar, Nathalie Y R Agar, Jakal Amin, Jared R Auclair, Rutali R Brahme, Marcela de Barros, David J Greenblatt, Md Amin Hossain, Roman Manetsch, Carla Mattos, Brandon C Miller, Jaime L Schneider, Qingping Wang

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: England : Nature communications , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 469099

 Covalent drug discovery efforts are growing rapidly but have major unaddressed limitations. These include high false positive rates during hit-to-lead identification
  the inherent uncoupling of covalent drug concentration and effect [i.e., uncoupling of pharmacokinetics (PK) and pharmacodynamics (PD)]
  and a lack of bioanalytical and modeling methods for determining PK and PD parameters. We present a covalent drug discovery workflow that addresses these limitations. Our bioanalytical methods are based upon a mass spectrometry (MS) assay that can measure the percentage of drug-target protein conjugation (% target engagement) in biological matrices. Further we develop an intact protein PK/PD model (iPK/PD) that outputs PK parameters (absorption and distribution) as well as PD parameters (mechanism of action, protein metabolic half-lives, dose, regimen, effect) based on time-dependent target engagement data. Notably, the iPK/PD model is applicable to any measurement (e.g., bottom-up MS and other drug binding studies) that yields % of target engaged. A Decision Tree is presented to guide researchers through the covalent drug development process. Our bioanalytical methods and the Decision Tree are applied to two approved drugs (ibrutinib and sotorasib)
  the most common plasma off-target, human serum albumin
  three protein targets (KRAS, BTK, SOD1), and to a promising SOD1-targeting ALS drug candidates.
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