Tetracycline as an inhibitor to the SARS-CoV-2

Abstract

The coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains an extant threat against public health on a global scale. Cell infection begins when the spike protein of SARS-CoV-2 binds with the human cell receptor, angiotensin-converting enzyme 2 (ACE2). Here, we address the role of tetracycline as an inhibitor for the receptor-binding domain (RBD) of the spike protein. Targeted molecular investigation show that tetracycline binds more favorably to the RBD (-9.40 kcal/mol) compared to doxycycline (-8.08 kcal/mol), chloroquine (-6.31 kcal/mol), or gentamicin (-4.83 kcal/mol) while inhibiting attachment to ACE2 to a greater degree (binding efficiency of 2.98 kcal/(mol nm² ) for tetracycline-RBD, 5.16 kcal/(mol nm² ) for doxycycline-RBD, 5.59 kcal/(mol nm² ) for chloroquine-RBD, and 7.02 kcal/(mol nm² ) for gentamicin-RBD. Stronger inhibition by tetracycline is verified with nonequilibrium PMF calculations, for which the tetracycline-RBD complex exhibits the lowest free energy profile along the dissociation pathway from ACE2. Tetracycline binds to tyrosine and glycine residues on the viral contact interface that are known to modulate molecular recognition and bonding affinity. These RBD residues also engage in significant hydrogen bonding with the human receptor ACE2. The ability to preclude cell infection complements the anti-inflammatory and cytokine suppressing capability of tetracycline; this may reduce the duration of ICU stays and mechanical ventilation induced by the coronavirus SARS-CoV-2.

Keywords: COVID-19; Coronavirus; SARS-CoV-2; tetracycline.

Figure 1

(A) RMSD plots of the RBD–ACE2 complex with and without the presence of small molecule inhibitors. The dynamic stability of the tetracycline–RBD:ACE2 structure appears distinctly lower than the uninhibited case, suggesting that the bound state is highly unfavorable. (B) RMSF of the RBD:ACE2 complex with and without inhibitors. (C) RMSD graphs of the inhibitor–RBD complex. Initial structures after equilibration are confirmed to be stable. (D) RMSF of the RBD when bound to small molecule inhibitors. Each structure is again shown to be stable over the trajectories run. ACE2, angiotensin‐converting enzyme 2; RBD, receptor‐binding domain; RMSD, root mean square deviation; RMSF, root mean square fluctuation

Figure 2

Interaction map of amino acid residues of the severe acute respiratory syndrome coronavirus 2 RBD that have the highest binding affinity with tetracycline. The Tyr 449, Asn 501, Gly 496, and Tyr 505 residues have also been shown to form persistent hydrogen bonds in maintaining the RBD–ACE2 complex. ACE2, angiotensin‐converting enzyme 2; RBD, receptor‐binding domain

Figure 3

The hydrogen bonding lifetimes of binding site residues of the inhibited RBD with ACE2 sustained in 100 ns of simulation time, normalized by hydrogen bonding lifetimes in the uninhibited RBD–ACE2 complex. ACE2, angiotensin‐converting enzyme 2; RBD, receptor‐binding domain

Figure 4

The PMF as a function of the distance between the centers of masses of the spike protein RBD complexes and the cell receptor ACE2. The tetracycline–RBD complex exhibits the lowest free energy profile along the dissociation pathway. ACE2, angiotensin‐converting enzyme 2; PMF, potential of mean force; RBD, receptor‐binding domain