In Silico Screening, In Vitro Mpro Inhibitory, and Adjunctive Therapy Value of Minocycline for the Treatment of COVID-19.

What Is Known and Objective. Novel coronavirus disease (COVID-19) is still ravaging globally since its first discovery in 2019. With the continuous emergence of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) mutant strains, therapeutic entities are still needed to be discovered. This study was to explore SARS-CoV-2 inhibitors and therapeutic entities for COVID-19. Methods. Based on Lipinski's rule of 5, a small-scale "old" drug database (clinical drugs being used in Ordos Central Hospital) was established, and in silico screening of M^pro inhibitors was conducted. Binding affinity and interaction as well as structure-affinity relationship were analyzed. Furthermore, molecular dynamic (MD) simulation of the selected drugs was performed to understand the conformational changes in docked complex. In vitro M^pro inhibition tests were performed according to established methods. Finally, literature review of potential "old" drug for the treatment of COVID-19 was conducted. Results and Discussion. The antibiotic minocycline, an inhibitor of bacterial ribosomal RNA, was screened out which showed the highest binding affinity (−9.6 kcal/mol). Beside the hydrogen bond with Cys145 and hydrophobic interactions, minocycline formed a pi-cation with His41, which strongly supported minocycline as a Michael addition acceptor to bind with the catalytic site of M^pro. MD simulation results show that minocycline displayed less conformational changes. The structure-affinity relationship was summarized based on minocycline analogs, and minocycline showed in vitro M^pro inhibitory activity with IC₅₀ of 5 mM. More importantly, the literature review found that minocycline had both in vitro and in vivo broad-spectrum antiviral as well as anti-inflammatory activities, and the levels of a broad spectrum of biological markers during minocycline administration were opposed to those of COVID-19 conditions (both severe and nonsevere). What is New and Conclusion. Minocycline deserves an adjunctive therapeutic option for COVID-19 condition (both severe and nonsevere). This study shed a new light on drug-repurposing strategy for the viral disease. [ABSTRACT FROM AUTHOR]