Tetracycline as an inhibitor to the coronavirus SARS-CoV-2

TL;DR

This study investigates Tetracycline's potential to inhibit SARS-CoV-2 by binding to its spike protein's RBD, showing it binds more favorably than other drugs and could reduce viral attachment and infection.

Contribution

The paper provides molecular evidence that Tetracycline effectively inhibits SARS-CoV-2 RBD binding to ACE2, suggesting its potential as a therapeutic agent against COVID-19.

Findings

Tetracycline binds more favorably to RBD than Chloroquine or Doxycycline.

Tetracycline inhibits RBD attachment to ACE2 more effectively.

Molecular simulations show Tetracycline lowers free energy along dissociation pathways.

Abstract

The coronavirus 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 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 Chloroquine (-6.31 kcal/mol) or Doxycycline (-8.08 kcal/mol) and inhibits attachment to ACE2 to a greater degree (binding efficiency of 2.98 $\frac{\text{kcal}}{\text{mol}\cdot \text{nm}^2}$ for Tetracycline-RBD, 5.59 $\frac{\text{kcal}}{\text{mol}\cdot \text{nm}^2}$ for Chloroquine-RBD, 5.16 $\frac{\text{kcal}}{\text{mol}\cdot \text{nm}^2}$ for Doxycycline-RBD). Stronger Tetracycline inhibition 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 appears to target viral residues that are usually involved in significant hydrogen bonding with ACE2; this inhibition of cellular infection complements the anti-inflammatory and cytokine suppressing capability of Tetracycline, and may further reduce the duration of ICU stays and mechanical ventilation induced by the coronavirus SARS-CoV-2.