Combining computational and experimental evidence on the activity of antimalarial drugs on papain‐like protease of SARS‐CoV‐2: A repurposing study

Abstract

The development of inhibitors that target the papain‐like protease (PLpro) has the potential to counteract the spread of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the agent causing coronavirus disease 2019 (COVID‐19). Based on a consideration of its several downstream effects, interfering with PLpro would both revert immune suppression exerted by the virus and inhibit viral replication. By following a repurposing strategy, the current study evaluates the potential of antimalarial drugs as PLpro inhibitors, and thereby the possibility of their use for treatment of SARS‐CoV‐2 infection. Computational tools were employed for structural analysis, molecular docking, and molecular dynamics simulations to screen antimalarial drugs against PLpro, and in silico data were validated by in vitro experiments. Virtual screening highlighted amodiaquine and methylene blue as the best candidates, and these findings were complemented by the in vitro results that indicated amodiaquine as a μM PLpro deubiquitinase inhibitor. The results of this study demonstrate that the computational workflow adopted here can correctly identify active compounds. Thus, the highlighted antimalarial drugs represent a starting point for the development of new PLpro inhibitors through structural optimization.

Identification of SARS-CoV-2 Main Protease Inhibitors Using Chemical Similarity Analysis Combined with Machine Learning

“…First, from the literature, we identified anti-coronavirus compounds with diverse mechanisms of action ( Table S1 ) to be used as references for similarity searching from a compound screening library with ~17 million molecules of bioactive compounds, natural products, and peptides [ 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. Of the 62 reference molecules, thirteen ( Table S2 ) have been shown to inhibit at least one of two SARS-CoV-2 proteases [ 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ]. Using three different molecular fingerprints, we identified 632,149 unique molecules that had similarity values greater than the mean plus three standard deviations (SDs) for all three of the molecular fingerprints.…”

Applicability of Redirecting Artemisinins for New Targets

“…[ 111 ] Methods based on ARTS screening via computational approaches, including proteomics, transcriptomics, and bioinformatics strategies to identify drug candidates, should be considered. [ 61 ] From there, advanced docking techniques and high‐throughput selection, [ 2 ] targeting a specific pathogen and its metabolism, as well as the affected organs, may result in improved outcomes ( Figure 6 ). The COVID pandemic provided examples of the unfortunate consequences of repurposing drugs without sufficient attention to systematic evaluation of this kind – for example, the controversial use of hydroxychloroquine.…”

“…Overall, attempts at repurposing drugs (approved for human administration) or redirecting (not yet approved) against COVID‐19 have not been fruitful, possibly because of the small number of compounds tested using classical experimental approaches and the reliance on a limited set of factors that were used to predict the relevance of the drugs that were being considered. [ 67 ] To try to overcome these deficiencies, Ribaudo and colleagues [ 61 ] used computational methods to examine anti‐malarial drugs that may target the papain‐like protease (PLpro) of SARS‐CoV‐2. ARTS and amodiaquine were selected for further analysis by binding site profiling, induced‐fit docking, and molecular dynamics.…”

“…Currently, a limited number of drugs are approved for treatment of COVID-19, [56] namely, the anti-protease PAXLOVID [57] and the nucleoside analogs Molnupiravir and Remdesivi [58] The pathology of this viral disease has some similarities to that of malarial acute respiratory distress syndrome, in that the lungs are the main target organ, and the injury and death are immunemediated, rather than pathogen-mediated. [59,60] Consequently, ARTS treatment against COVID-19 has been proposed, based on its anti-inflammatory activity, [8,9,38,61] inactivation of viral papainlike protease [62] and also the specific binding of artesunate to the spike protein of SARS-CoV-2 (Figure 2, docking). So far, few experiments have been conducted to assess the effect of ARTS on COVID-19.…”

Investigation on the Essential Oils of the Achillea Species: From Chemical Analysis to the In Silico Uptake against SARS-CoV-2 Main Protease

“…The active sites of the viral targets were set as search spaces for targeted docking. Finally, 250 runs of molecular docking according to the Lamarckian genetic algorithm were performed for ligands that met the conditions of the first step of the docking protocol [ 63 ]. Discovery studio 4.5 was used for the 3D visualizations of the results, and LigPlot + V.2.2 was applied for the 2D presentations.…”