Nicotinic cholinergic system and COVID-19: In silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions

Abstract

SARS-CoV-2 infection was announced as a pandemic in March 2020. Since then, several scientists have focused on the low prevalence of smokers among hospitalized COVID-19 patients. These findings led to our hypothesis that the Nicotinic Cholinergic System (NCS) plays a crucial role in the manifestation of COVID-19 and its severe symptoms. Molecular modeling revealed that the SARS-CoV-2 Spike glycoprotein might bind to nicotinic acetylcholine receptors (nAChRs) through a cryptic epitope homologous to snake toxins, substrates well documented and known for their affinity to the nAChRs. This binding model could provide logical explanations for the acute inflammatory disorder in patients with COVID-19, which may be linked to severe dysregulation of NCS. In this study, we present a series of complexes with cholinergic agonists that can potentially prevent SARS-CoV-2 Spike glycoprotein from binding to nAChRs, avoiding dysregulation of the NCS and moderating the symptoms and clinical manifestations of COVID-19. If our hypothesis is verified by in vitro and in vivo studies, repurposing agents currently approved for smoking cessation and neurological conditions could provide the scientific community with a therapeutic option in severe COVID-19.

Keywords: ACh, Acetylcholine; AChBP, Acetylcholine-binding protein; ARDS, acute respiratory distress syndrome; BLAST, Basic Local Alignment Search Tool; CHARMM, Chemistry at Harvard Macromolecular Mechanics; CNS, Central Nervous System; COVID-19; Cholinergic agonists; CoV, coronavirus; DCD, single precision binary FORTRAN; ECD, extracellular domain; HADDOCK, High Ambiguity Driven protein-protein DOCKing; HMGB1, High-mobility group protein 1; IL, Interleukin; Jak2, Janus kinases 2; LBD, Ligand Binding Domain; MD, Molecular Dynamics; MDS, Molecular Dynamics Simulations; MERS, Middle East Respiratory Syndrome; NAMD, Nanoscale Molecular Dynamics; NCBI, National Center for Biotechnology Information; NCS, Nicotinic Cholinergic System; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; NPT, constant number, pressure, energy; NVT, constant number, volume, energy; Nicotinic acetylcholine receptors; PDB, Protein Data Bank; PME, Particle Mesh Ewald; PRODIGY, PROtein binDIng enerGY prediction; PyMOL, Python Molecule; RBD, Receptor Binding Domain; RMSD, Root-mean-square deviation; SARS, Severe Acute Respiratory Syndrome; SARS-CoV-2; SARS-CoV-2 S1, SARS - 2 Spike Subunit 1 protein; STAT3, signal transducer and activator of transcription 3; STD NMR, Saturation Transfer Difference Nuclear Magnetic Resonance; Spike glycoprotein; TNF, Tumor Necrosis Factor; VMD, Visual Molecular Dynamics; lig, ligand; nAChRs, nicotinic acetylcholine receptors.

Graphical abstract

Fig. 1

Schematic workflow of our in-silico approach.

Fig. 2

Sequence alignments of α7 nAChR (PDB: P36544) along with the respective coordinating structures. A. Nicotine (1UW6), B. Varenicline (4AFT), C. Cytisine (4BQT), D. Epibatidine (2BYN), and E.α-Conotoxin (5T90). Colored aa: conserved in human nAChR α7 subunit sequence, coordinating the respective agonist/antagonist compounds (Yellow: varenicline/cytisine, Magenta: epibatidine, Cyan: α-conotoxin, Green: nicotine). Framed aa: conserved among human nAChR α7 subunit LBD, SARS- -2 Spike glycoprotein, and AChBP.

Fig. 3

Protein complexes of the AChBP, RBD of SARS-CoV-2 Spike glycoprotein, and cholinergic agonists. A. Nicotine, B. Nicotine with a surface presentation, C. Nicotine and α7 nAChR shown in both bound and unbound (i.e., apo) structure, D. α-Conotoxin, E. Varenicline, F. Cytisine, G. Epibatidine.

Fig. 4

Model of S1 to nAChR-α7 dimer interaction after 20 ns MDS. Chain F (S1) in magenta, chain A (a7) in green, and chain B (a7) in cyan. Figure generated with PyMol [49].

Fig. 5

The local ligand environment in the S1-nAChR-α7-dimer ligand complexes, one panel for each ligand. Ligands are shown in yellow. Residues of the α7 chains A and B are in green and cyan, respectively, while S1 residues are shown in magenta. Yellow dots represent polar interactions.