Minocycline Might Be an Adjunctive Therapy Option for the Treatment of COVID-19: In Silico Screening, Structure-affinity Relationship, and Literature Review

Up to now, there is no specific therapy for the globally ongoing COVID-19. To explore potential inhibitors of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) for the treatment of novel coronavirus disease (COVID-19), in silico screening of 135 clinical drugs was performed targeting on 3-chymotrypsin-like protease (3CLpro, or M pro ). Six drugs including anti-HIV drug (raltegravir), antibacterial drugs (cefonicid, cefoperazone, minocycline), and antidiabetic drugs (canaglifozin, glyburide) showed high binding affinities (≤ -8.5 kcal/mol) and interesting binding conformations compared with the designed co-crystal ligand N3 (-7.7 kcal/mol). In which the antibiotic minocycline, an inhibitor of bacterial ribosomal rRNA, showed the highest binding affinity (-9.6 kcal/mol). Valuable hydrogen bonding and hydrophobic interactions were found between minocycline and M pro active site. Beside the hydrogen bond with Cys145, 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 . The structure-affinity relationship was studied based on molecular docking of minocycline analogues. 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 condition (both severe and non-severe). Minocycline deserves in vitro and in vivo evaluations as SARS-CoV-2 inhibitor as well as a randomized controlled trial to investigate the efficacy for COVID-19. These studies will shed new light on an adjuvant treatment strategy for this potentially lethal viral disease.