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?:abstract
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OBJECTIVE The repurposing of nitazoxanide, doxycycline, and azithromycin may be effective to improve the symptoms in mild and moderate COVID-19 subjects. This study aimed to detect and explain the efficacy of reusing of these drugs in treating COVID-19. METHODS The study was divided into two parts; clinical and computational parts. In the clinical part, 80 (30 females) subject with reverse transcription-polymerase chain reaction confirmed COVID-19 with mild and moderate symptoms were enrolled in the study. Subjects were treated with azithromycin or doxycycline, and nitazoxanide were added to the treatment if the subject had diarrhea. Subjects were divided into 4 groups: Group 1: subjects treated with azithromycin (20 subjects); Group 2: subjects treated with doxycycline (20 subjects); Group 3: subjects treated with a combination of nitazoxanide and doxycycline (20 subjects); and Group 4: subjects treated with a combination of nitazoxanide and azithromycin (20 subjects). In the computational part, we docked the three drugs against all currently available COVID-19 related protein targets (viral and non-viral). Subsequently, top hits were subjected to molecular dynamic simulations (50 ns) and binding free energy calculations to further validate the docking experiments and to investigate the binding modes of the potential inhibitors. RESULTS The symptomatic improvement of mild to moderate subjects was seen on the 5th day after starting treatment in Group 3 and Group 4 and on the 7th day in Group 2. However, for Group 1, the symptomatic improvement of mild to moderate subjects was not seen on the 5th day and required replacement by doxycycline to get the symptomatic improvement. None of the subjects needed intensive care admission and no deaths were reported. In silico, results were in good accordance with the clinical outcomes, where both nitazoxanide and doxycycline achieved the best docking scores against the viral ADP-ribose phosphatase (ADPRP) and the human Adaptor-Associated Kinase 1 (AAK1). Molecular dynamic simulations revealed that both drugs were stable in their bindings indicating that they can be considered as lead molecules for targeting ADPRP and AAK1. CONCLUSION The clinical and computational studies applied on three FDA-approved antimicrobials together with their recent clinical findings revealed that both nitazoxanide and doxycycline have great therapeutic potential against COVID-19. The future in-vitro mechanistic investigation may confirm our primary computational outcomes, and in turn, these classes of compounds provide a promising starting point for further anti-COVID-19 therapeutics.
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