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

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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.

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Acknowledgements

Financial support is gratefully acknowledged for the National Natural Science Foundation of China (91853101, 81922070, and 81973286), the Natural Science Foundation of Liaoning Province (2019-YQ-07), the Dalian Science and Technology Innovation Foundation (2019J11CY019), Shanghai Talent Development Fund (2019093), the grant from DICP (DICP I202007), and the National Key R&D Program of China (2019YFE0119300 and 2018YFC1706600).

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Authors and Affiliations

  1. CAS Key Laboratory of Separation Sciences for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023, Liaoning, China

    Shirui Yang, Wenxiang Zhang, Zheyi Liu, Ziyang Zhai & Fangjun Wang

  2. University of Chinese Academy of Sciences, Beijing, 100049, China

    Shirui Yang & Fangjun Wang

  3. Department of Chemistry, Zhejiang University, Hangzhou, 310028, Zhejiang, China

    Wenxiang Zhang

  4. Institute of Interdisciplinary Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China

    Xudong Hou, Ping Wang & Guangbo Ge

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  1. Shirui Yang
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  2. Wenxiang Zhang
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  4. Ziyang Zhai
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  5. Xudong Hou
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  7. Guangbo Ge
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  8. Fangjun Wang
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Contributions

Conceptualization: [Shirui Yang], [Fangjun Wang]; Methodology: [Shirui Yang], [Zheyi Liu], [Wenxiang Zhang]; Validation: [Shirui Yang], [Wenxiang Zhang]; Formal analysis and investigation: [Shirui Yang], [Wenxiang Zhang], [Ziyang Zhai]; Data curation: [Shirui Yang]; Visualization: [Shirui Yang], [Wenxiang Zhang]; Writing - original draft preparation: [Shirui Yang]; Resources: [Fangjun Wang], [Xudong Hou], [Ping Wang], [Guangbo Ge]; Writing - review and editing: [Wenxiang Zhang], [Guangbo Ge], [Fangjun Wang]; Project administration: [Fangjun Wang], [Guangbo Ge]; Supervision: [Fangjun Wang], [Guangbo Ge].

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Yang, S., Zhang, W., Liu, Z. et al. Lysine reactivity profiling reveals molecular insights into human serum albumin–small-molecule drug interactions. Anal Bioanal Chem 413, 7431–7440 (2021). https://doi.org/10.1007/s00216-021-03700-1

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