Discovery of a new generation of angiotensin receptor blocking drugs: Receptor mechanisms and in silico binding to enzymes relevant to SARS-CoV-2

Harry Ridgway, Graham J. Moore, Thomas Mavromoustakos, Sotirios Tsiodras, Irene Ligielli, Konstantinos Kelaidonis, Christos T. Chasapis, Laura Kate Gadanec, Anthony Zulli, Vasso Apostolopoulos, Russell Petty, Ioannis Karakasiliotis, Vassilis G. Gorgoulis, John M. Matsoukas (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
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Abstract

The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as "bisartans" is reported. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2 + domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681-686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric "warhead" of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid).

Original languageEnglish
Pages (from-to)2091-2111
Number of pages21
JournalComputational and structural biotechnology journal
Volume20
Early online date9 Apr 2022
DOIs
Publication statusPublished - 2022

Keywords

  • Angiotensin receptors
  • Animal AT1 receptor studies
  • Bisartan NMR studies
  • Bisartans tetrazole
  • Docking RBD/ACE2 studies
  • SARS-CoV-2 spike/ACE2 complex blockers
  • Sartans

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