In silico Study of Azithromycin, Chloroquine and Hydroxychloroquine and their Potential Mechanisms of Action against SARS-CoV-2 Infection

Abstract The coronavirus disease 19 (COVID-19) is a highly transmissible viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical trials have reported an improved outcome resulting from effective reduction or absence of viral load when patients were treated with chloroquine or hydroxychloroquine. In addition, these drugs had their effects improved by simultaneous azithromycin administration. The Receptor-Binding Domain of SARS-CoV Spike Protein (RBD of S Protein) binds to the cell surface angiotensin-converting enzyme 2 (ACE2) receptors allowing viral entry and replication into the host cells. The viral Main Protease (Mpro) and the Cathepsin L (CTSL) are among the proteolytic systems involved in S Protein activation by SARS-CoV-2. Hence, molecular docking studies were performed to test the binding performance of these three drugs against four targets. Our finding showed azithromycin affinity scores (∆G) with strong interactions with ACE2, CTSL, Mpro and RBD. Chloroquine affinity scores showed 3 low energy results (less negative) with ACE2, CTSL and RBD; and a firm bond score with Mpro. With hydroxychloroquine, two results (ACE2 and Mpro) were firmly bound to the receptors; however, CTSL and RBD showed low interaction energies. The differences in better interactions and affinity between hydroxychloroquine and chloroquine with ACE2 and Mpro were probably due to structural differences between the drugs. Azithromycin, on other hand, 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.