In silico study of azithromycin, chloroquine and hydroxychloroquine and their potential mechanisms of action against SARS-CoV-2 infection

Abstract

Coronavirus disease 2019 (COVID-19) is a highly transmissible viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical trials have reported improved outcomes resulting from an effective reduction or absence of viral load when patients were treated with chloroquine (CQ) or hydroxychloroquine (HCQ). In addition, the effects of these drugs were improved by simultaneous administration of azithromycin (AZM). The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein binds to the cell surface angiotensin-converting enzyme 2 (ACE2) receptor, allowing virus entry and replication in host cells. The viral main protease (M^pro) and host cathepsin L (CTSL) are among the proteolytic systems involved in SARS-CoV-2 S protein activation. Hence, molecular docking studies were performed to test the binding performance of these three drugs against four targets. The findings showed AZM affinity scores (ΔG) with strong interactions with ACE2, CTSL, M^pro and RBD. CQ affinity scores showed three low-energy results (less negative) with ACE2, CTSL and RBD, and a firm bond score with M^pro. For HCQ, two results (ACE2 and M^pro) were firmly bound to the receptors, however CTSL and RBD showed low interaction energies. The differences in better interactions and affinity between HCQ and CQ with ACE2 and M^pro were probably due to structural differences between the drugs. On other hand, AZM not only showed more negative (better) values in affinity, but also in the number of interactions in all targets. Nevertheless, further studies are needed to investigate the antiviral properties of these drugs against SARS-CoV-2.

Keywords: Azithromycin; COVID-19; Chloroquine; Coronavirus; Hydroxychloroquine; Molecular docking.

Fig. 1

Graphical representation of binding energies (ΔG, in kcal/mol) of molecular docking between the ligands [azithromycin, chloroquine and hydroxychloroquine] and targets [angiotensin-converting enzyme 2 (ACE2), cathepsin L (CTSL), viral main protease (M^pro) and the receptor-binding domain (RBD)] calculated by AutoDock Vina^Ⓡ software.

Fig. 2

Interactions established in two dimensions in Biovia Discovery Studio^Ⓡ 4.5 software after docking between azithromycin and angiotensin-converting enzyme 2 (ACE2), cathepsin L (CTSL), viral main protease (M^pro) and the receptor-binding domain (RBD). Coupling scores are listed on each complex to reflect the binding power. Receptor amino acids are represented by spheres of different colours around the structure. The H-bonds are shown as dashed green lines (darker colour), while the other dashed lines represent hydrophobic interactions and other types of intermolecular interactions.

Fig. 3

Interactions established in two dimensions in Biovia Discovery Studio^Ⓡ 4.5 software after docking between chloroquine and angiotensin-converting enzyme 2 (ACE2), cathepsin L (CTSL), viral main protease (M^pro) and the receptor-binding domain (RBD). Coupling scores are listed on each complex to reflect the binding power. Receptor amino acids are represented by spheres of different colours around the structure. The H-bonds are shown as dashed green lines (darker colour), while the other dashed lines represent hydrophobic interactions and other types of intermolecular interactions.

Fig. 4

Interactions established in two dimensions in Biovia Discovery Studio^Ⓡ 4.5 software after docking between hydroxychloroquine and angiotensin-converting enzyme 2 (ACE2), cathepsin L (CTSL), viral main protease (M^pro) and the receptor-binding domain (RBD). Coupling scores are listed on each complex to reflect the binding power. Receptor amino acids are represented by spheres of different colours around the structure. The H-bonds are shown as dashed green lines (darker colour), while the other dashed lines represent hydrophobic interactions and other types of intermolecular interactions.

Fig. 5

Best affinity interactions established after coupling the drugs azithromycin (AZM), chloroquine (CQ) and hydroxychloroquine (HCQ) with receptors for the proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a three-dimensional format. The H-bonds are shown as green lines, while hydrophobic interactions are the remaining lines. Residues are identified by abbreviations/numbering in each field, and the fitting scores are listed in each complex. (A–D) Interaction between AZM and ACE2 (A), CTSL (B), M^pro (C) and RBD (D); (E) interaction between CQ and M^pro; and (F,G) interaction between HCQ and ACE2 (F) and M^pro (G). ACE2, angiotensin-converting enzyme 2; CTSL, cathepsin L; M^pro, viral main protease; RBD, receptor-binding domain.