Computational Repurposing of Drugs and Natural Products Against SARS-CoV-2 Main Protease (Mpro) as Potential COVID-19 Therapies

Abstract

We urgently need to identify drugs to treat patients suffering from COVID-19 infection. Drugs rarely act at single molecular targets. Off-target effects are responsible for undesirable side effects and beneficial synergy between targets for specific illnesses. They have provided blockbuster drugs, e.g., Viagra for erectile dysfunction and Minoxidil for male pattern baldness. Existing drugs, those in clinical trials, and approved natural products constitute a rich resource of therapeutic agents that can be quickly repurposed, as they have already been assessed for safety in man. A key question is how to screen such compounds rapidly and efficiently for activity against new pandemic pathogens such as SARS-CoV-2. Here, we show how a fast and robust computational process can be used to screen large libraries of drugs and natural compounds to identify those that may inhibit the main protease of SARS-CoV-2. We show that the shortlist of 84 candidates with the strongest predicted binding affinities is highly enriched (≥25%) in compounds experimentally validated in vivo or in vitro to have activity in SARS-CoV-2. The top candidates also include drugs and natural products not previously identified as having COVID-19 activity, thereby providing leads for experimental validation. This predictive in silico screening pipeline will be valuable for repurposing existing drugs and discovering new drug candidates against other medically important pathogens relevant to future pandemics.

Identifying SARS-CoV-2 Drugs Binding to the Spike Fatty Acid Binding Pocket Using In Silico Docking and Molecular Dynamics

“…Literature analysis of the modes of action of these classes, and published work on their efficacy against SARS-CoV-2, provide mechanistic information and validate our computational screening approach as useful for identifying repurposing candidates. This approach was adopted in our published repurposing studies on the SARS-CoV-2 main protease (M pro ), helicase, and RNA-dependent RNA polymerase [ 8 , 9 , 11 ].…”

“…We have reported computational studies on S protein and ACE2 to elucidate the origins of SARS-CoV-2 and identify repurposed drugs inhibiting its main protease, RNA-dependent RNA polymerase, and helicase [ 8 , 9 , 10 , 11 ]. Here, we used the S protein FABP structure to identify repurposing candidates as SARS-CoV-2 treatments.…”

A Study of Drug Repurposing to Identify SARS-CoV-2 Main Protease (3CLpro) Inhibitors

“…Cynarine, eravacycline, and prexasertib represented outstanding inhibitory activity with IC 50 values of 1.82 μ M, 1.65 μM, and 1.99 μM, respectively. Interestingly, eravacycline was also identified in recent virtual screens of FDA-approved drugs for repurposing as COVID-19 treatments [ 14 , 15 ]. The docking modes of cynarine, eravacycline, and prexasertib indicated that between the two catalytic dyad residues His41 and Cys145, Cys145 was involved in binding with all three chemicals ( Figure 4 ).…”

Comprehensive Consensus Analysis of SARS-CoV-2 Drug Repurposing Campaigns

“…Docking studies, similarly, largely favored prioritizing the M pro as the target in their screenings, although many drugs were demonstrated to have inhibitory effects against a different viral protein. Remdesivir, for example, which was cocrystallized with RdRp, appeared in numerous M pro computational docking campaigns as a predicted hit. − On the other hand, it is possible that identified drugs in a target-specific virtual repurposing campaign could act synergistically on more than one SARS-CoV-2 targeas speculated for chloroquine inhibiting M pro activity and interfering with the endosomal acidification process associated with SARS-CoV-2 viral entry . The lack of sufficient biochemical data, in turn, may render it challenging to rule out off-target activity.…”

“…These molecules were active in cell-based repurposing screenings: dolutegravir, elbasvir, nelfinavir, atazanavir, lopinavir, ritonavir, darunavir, saquinavir, indinavir, oseltamivir, chloroquine, and remdesivir (Figure ). ,,,,,,,,,,− ,,− …”