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Molecular insights into the AT1 antagonism based on biophysical and in silico studies of telmisartan

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Abstract

AT1 antagonists (SARTANs) constitute one of the most successful classes of antihypertensive agents. These molecules interfere with the renin angiotensin system by preventing the vasoconstrictive hormone angiotensin II from binding onto the AT1 receptor. It is proposed that SARTANs exert their biological action by inserting into the lipid membrane and then diffuse to the active site of AT1 receptor. In this article, the conformational properties of telmisartan are analyzed both in solution and in the active site of the AT1 receptor using conformational analysis, molecular docking, Molecular Dynamics (MD) simulations, and in silico Ala-scanning mutagenesis studies. Combined results reveal telmisartan’s crucial structural characteristics and classify the importance of receptor’s amino acids for ligand binding. Since telmisartan is exerting its activity on a transmembrane receptor, Differential Scanning Calorimetry was applied to study the drug effects in lipid bilayers mimicking the biological membrane environment. Of paramount importance, is the finding that telmisartan exerted similarities but also significant differences with other AT1 antagonists on the basis of their interaction with lipid bilayers and subsequent docking into the active site. This could in part explain their similar mode of action and in parallel their distinct pharmacological profile.

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Acknowledgments

We acknowledge (a) the State Scholarships Foundation of Greece; (b) Boehringer Ingelheim pharmaceuticals for the kind donation of telmisartan; and (c) European Union’s Seventh Framework Programme (FP7-REGPOT-2009-1) under Grant agreement no. 245866. Finally, SGG acknowledges the support from EN-FIST Centre of Excellence and Slovenian Research Agency.

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Authors and Affiliations

  1. National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry and Biotechnology, Vassileos Constantinou 48, 116 35, Athens, Greece

    Eftichia Kritsi, Constantinos Potamitis, Panagiotis Zoumpoulakis & Thomas Mavromoustakos

  2. Department of Biophysics, Faculty of Medicine, Bahçeşehir University, Beşiktaş, Istanbul, Turkey

    Serdar Durdagi

  3. Laboratory of Biomolecular Structure, National Institute of Chemistry, Ljubljana, Slovenia

    Simona Golic Grdadolnik

  4. Chemistry Department, Kapodistrian University of Athens, Athens, Greece

    Eftichia Kritsi & Thomas Mavromoustakos

  5. EN-FIST Centre of Excellence, Ljubljana, Slovenia

    Simona Golic Grdadolnik

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  1. Eftichia Kritsi
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  2. Constantinos Potamitis
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  3. Serdar Durdagi
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  4. Panagiotis Zoumpoulakis
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  5. Simona Golic Grdadolnik
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  6. Thomas Mavromoustakos
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Correspondence to Panagiotis Zoumpoulakis.

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Kritsi, E., Potamitis, C., Durdagi, S. et al. Molecular insights into the AT1 antagonism based on biophysical and in silico studies of telmisartan. Med Chem Res 22, 4842–4857 (2013). https://doi.org/10.1007/s00044-012-0464-5

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