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

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)

Structural elucidation and conformational properties of the toxin paralysin beta-Ala-Tyr

Journal URL: http://www.sciencedirect.com/science/journal/0731708

Molecular dynamics at the receptor level of immunodominant myelin basic protein epitope 87-99 implicated in multiple sclerosis and its antagonists altered peptide ligands: Triggering of immune response

This work reports molecular dynamics studies at the receptor level of the immunodominant myelin basic protein (MBP) epitope 87–99 implicated in multiple sclerosis, and its antagonists altered peptide ligands (APLs), namely [Arg91, Ala96] MBP87–99 and [Ala91,96] MBP87–99. The interaction of each peptide ligand with the receptor human leukocyte antigen HLA-DR2b was studied, starting from X-ray structure with pdb code: 1ymm. This is the first such study of APL-HLA-DR2b complexes, and hence the first attempt to gain a better understanding of the molecular recognition mechanisms that underlie TCR antagonism by these APLs. The amino acids His88 and Phe89 serve as T-cell receptor (TCR) anchors in the formation of the trimolecular complex TCR-peptide-HLA-DR2b, where the TCR binds in a diagonal, off-centered mode to the peptide-HLA complex. The present findings indicate that these two amino acids have a different orientation in the APLs [Arg91, Ala96] MBP87–99 and [Ala91,96] MBP87–99: His88 and Phe89 remain buried in HLA grooves and are not available for interaction with the TCR. We propose that this different topology could provide a possible mechanism of action for TCR antagonism

Studies on the thermotropic effects of cannabinoids on phosphatidylcholine bilayers using differential scanning calorimetry and small angle X-ray diffraction

Journal URL: http://www.sciencedirect.com/science/journal/0005273

Role of the Nh2-Terminal Domain of Angiotensin-Ii (Ang-Ii) and [Sar(1)]Angiotensin-Ii on Conformation and Activity - Nmr Evidence for Aromatic Ring Clustering and Peptide Backbone Folding Compared with [Des-1,2,3]Angiotensin-Ii

Journal URL: http://www.jbc.org

Authenticity of the traditional cypriot spirit "zivania" on the basis of H-1 NMR spectroscopy diagnostic parameters and statistical analysis

Journal URL: http://pubs.acs.org/journals/jafcau/index.htm

Design and synthesis of thrombin receptor-derived nonpeptide mimetics utilizing a piperazine scaffold

Journal URL: http://www.sciencedirect.com/science/journal/0968089