In silico Potential of Approved Antimalarial Drugs for Repurposing Against COVID-19

Abstract

Although the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is wreaking havoc and resulting in mortality and morbidity across the planet, novel treatments are urgently needed. Drug repurposing offers an innovative approach in this context. We report here new findings on the in silico potential of several antimalarial drugs for repurposing against COVID-19. We conducted analyses by docking the compounds against two SARS-CoV-2-specific targets: (1) the receptor binding domain spike protein and (2) the main protease of the virus (M Pro) using the Schrödinger software. Importantly, the docking analysis revealed that doxycycline (DOX) showed the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the present study. The in silico approach reported here suggested that DOX could potentially be a good candidate for repurposing for COVID-19. In contrast, to decipher the actual potential of DOX and halofantrine against COVID-19, further in vitro and in vivo studies are called for. Drug repurposing warrants consideration as a viable research and innovation avenue as planetary health efforts to fight the COVID-19 continue.

In Vitro Antiviral Activity of Doxycycline against SARS-CoV-2

“…The inhibition of both entry and viral replication after SARS-CoV-2 entry is consistent with the results from combinatorial computational approaches. Docking analysis showed that doxycycline could strongly bind the spike protein (S) of SARS-CoV-2 [41]. The spike viral protein of SARS-CoV-2 used the ACE-2 receptor for entry [42].…”

A pharmacovigilance study to quantify the strength of association between the combination of antimalarial drugs and azithromycin and cardiac arrhythmias: implications for the treatment of COVID-19.

“…These results go beyond the already known potential for HCQ and azithromycin to induce cardiac arrhythmias described in the medications’ SPC as these suspected associations are quantified in the current study using a large pharmacovigilance database (FAERS) and labeled as safety signals specifically in the context of COVID-19. For azithromycin, evidence from observational studies in regards to the association between macrolides and cardiovascular events is mixed [ 16 ].…”

“…Therefore, there is a critical need to examine safety signals for cardiac arrhythmias (QTp and TdP) from a pharmacovigilance perspective to ensure patient safety, especially in anticipation of high demand and use of CQ/HCQ and/or azithromycin in the war against COVID-19. Besides, several studies have investigated the use of other antimalarial drugs as candidates for repurposing, reemphasizing the importance of conducting pharmacovigilance studies [ 16 , 17 ]. Two pharmacovigilance studies assessed the risk of QTp and TdP following the use of HCQ/CQ and or azithromycin using data from the U.S. Food and Drugs Administration Adverse Event Reporting System (FAERS) [ 18 , 19 ].…”

Antimalarial Drugs and COVID -19

“…The in-silico potential of several antimalarial drugs for repurposing against COVID-19 has been reported, the antimalarial compounds were docked against two SARS-CoV-2-specific targets: the receptor binding domain spike protein and the main protease of the virus (MPro) using the Schro¨dinger software [5]. Doxycycline (DOX) exhibited the most effective binding to the spike protein of SARS-CoV-2, whereas halofantrine and mefloquine bound effectively with the main protease among the antimalarial drugs evaluated in the docking analysis [5] as indicated in table 2.…”

“…SARS-Cov-2 belong to the family of betacoronavirus , this includes already common viruses, Middle East respiratory syndrome (MERS) (2012) de Groot, et al [3] and Xiao, et al [4]. It is considered to be a bat virus; but, its intermediate host during transmission to humans is not proven [5].…”