B2-bradykinin receptor non-peptidic ligands as new drug-repurposing strategy against Covid-19 and other ARDS-inducing lung inflammatory infections

Abstract

INTRO: Dysregulation of kallikrein-bradykinin pathway has been linked to hyperinflammatory phase of several lung infections causing adult respiratory distress syndrome (ARDS) including COVID-19,SARS, MERS and Hantavirus Respiratory Syndrome. The injectable synthetic decapeptide Icatibant (Firazyr) is the only currently approved antagonist for B2-bradykinin receptor (B2-bkR), but its high cost makes it prohibitive for most healthcare systems of the region, particularly in the current pandemic context. AIM: To find small oral bioavailable, non-peptidic repurposing drug candidates for competitive inhibition of B2-bkR. M&M: By using 3 refined atomic models of B2-bkR obtained by homology and threading methods (SWISS-model/FG-MD and GPCR-I-TASSER) a high-throughput molecular docking (AutoDockVina) virtual screening was performed against all 2893 FDA-Approved, 3153 Investigational, 2414 in-trials and 440 harmless natural compounds (Drug Bank). Strong binders (Gbinding ≤ -11kcal/mol) were later scored by integrating the ligand-receptor contact forces (AutoDock tools, LigPlus) with the available toxicity, pharmacokinetic (FK) and pharmacodynamic (FD) data. By means of a high performance computing system (FIUNERcluster: 10 nodes, with 24 cores each), 20 nanoseconds molecular dynamics simulations (MDS) were run for top-10 ranked ligand-receptor complexes (NAMD/VMD). MDS trajectories were analysed by uni- and multivariate statistics using RMSD, RMSF, H-bonding and 2D-PCA as reaction coordinates (R). RESULTS & DISCUSSION: Starting from a large library of compounds, virtual screening achieved 41 putative ligands which, after filtering by FD, FK and thermodynamic criteria lead us to 6 oral-bioavailable and cost-effective promissory repurposing drugs. In order to experimentally test these candidates, a live cell imaging Ca2+ mobilization inhibition bioassay is under implementation.