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. 2021 Dec;413(30):7431-7440.
doi: 10.1007/s00216-021-03700-1. Epub 2021 Oct 21.

Lysine reactivity profiling reveals molecular insights into human serum albumin-small-molecule drug interactions

Shirui Yang  1   2 , Wenxiang Zhang  1   3 , Zheyi Liu  1 , Ziyang Zhai  1 , Xudong Hou  4 , Ping Wang  4 , Guangbo Ge  5 , Fangjun Wang  6   7
Affiliations

Lysine reactivity profiling reveals molecular insights into human serum albumin-small-molecule drug interactions

Shirui Yang et al. Anal Bioanal Chem. 2021 Dec.

Abstract

Human serum albumin (HSA) is one of the most important serum carrier proteins that deliver small-molecule drugs to their specific targets. Clarifying the molecular mechanism of the interaction between natural HSA and drugs in an aqueous solution has been a hot topic in pharmaceutical chemistry, clinical medicine, and biochemistry in recent years, but it is still challenging. In this paper, the details of molecular interactions of HSA with a variety of therapeutic drugs including ibuprofen, indomethacin, phenylbutazone, and warfarin are systematically investigated using a mass spectrometry (MS)-based lysine reactivity profiling (LRP) strategy. The results reaffirm that the major ligand binding sites (including Sites I and II) of HSA are located in subdomains IIA and IIIA, while several potential drug-binding areas at subdomain IIIB and α helix IIB-IIIA are newly characterized. The MS-LRP strategy may have important application prospects in pharmacodynamics, pharmacokinetics, and safety evaluation of small-molecule drugs.

Keywords: HSA–drug interaction; Human serum albumin; Lysine reactivity profiling; Mass spectrometry; Proteomics.

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