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  3. Systematic characterization of AT1 receptor antagonists with label-free dynamic mass redistribution assays

Systematic characterization of AT1 receptor antagonists with label-free dynamic mass redistribution assays

  • J Pharmacol Toxicol Methods. 2020 Mar-Apr;102:106682. doi: 10.1016/j.vascn.2020.106682.
Lala Qu 1,  Jixia Wang 2,  Tao Hou 3,  Han Zhou 3,  Zhiwei Wang 4,  Xiuli Zhang 5,  Xinmiao Liang 6
Affiliations

Affiliations

  • 1 Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; DICP-CMC Innovation Institute of Medicine, Taizhou 225300, China.
  • 3 Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
  • 4 DICP-CMC Innovation Institute of Medicine, Taizhou 225300, China.
  • 5 College of Pharmaceutical Sciences, Soochow University, Suzhou 215006, China; Qinghai Provincial Key Laboratory of Tibetan Medicine Research, Northwest Institute of Plateau Biology, Chinese Academy of Sciences, Xining 810008, China. Electronic address: zhangxl@sude.edu.cn.
  • 6 Key Lab of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; DICP-CMC Innovation Institute of Medicine, Taizhou 225300, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China. Electronic address: liangxm@dicp.ac.cn.
PMID: 32087363 DOI: 10.1016/j.vascn.2020.106682
Abstract

Introduction: In the drug discovery field, the binding affinities and binding kinetics of drug candidates are very important. Angiotensin II type 1 (AT1) receptor antagonists, e.g., candesartan, telmisartan, irbesartan, losartan and valsartan, show high affinities and long-lasting bindings to the receptor, making them preferred medications for hypertension treatment. However, the molecular binding properties of AT1 Receptor antagonists are controversial.

Methods: In this work, we established a profile to study the phenotypic properties of AT1 Receptor antagonists with label-free dynamic mass redistribution (DMR) assays in native human cells. With noninvasive features, DMR assay were conducted in multiple formats. Eleven antagonists were systematically evaluated with angiotensin II as an agonist probe in the Hep G2 cell line, which endogenously expresses the AT1 Receptor.

Results: The IC50 values to the AT1 Receptor of individual antagonist varied with different incubation times. The antagonists showed competitive behavior with angiotensin II. Schild analysis was used to analyze the competitive behavior of the antagonist. All of the antagonist showed long-lasting possession of the AT1 Receptor, except telmisartan. The systematic evaluation of the antagonists implied that 11 antagonists showed high binding affinity but distinct binding modes to AT1 Receptor.

Discussion: This study demonstrated that the DMR assay has great potential for determining the pharmacological parameters of ligands. This work may serve as guidance for other receptor and ligand assays.

Keywords

Angiotensin II type 1 receptor; Antagonist; Binding property; Dynamic mass redistribution assay.

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