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

ABSTRACT: 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 (mec

SUBMITTER: Hossain MA 

PROVIDER: S-EPMC11839910 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature