Sub-Micromolar Inhibition of SARS-CoV-2 3CLpro by Natural Compounds

Abstract

Inhibiting the main protease 3CLpro is the most common strategy in the search for antiviral drugs to fight the infection from SARS-CoV-2. We report that the natural compound eugenol is able to hamper in vitro the enzymatic activity of 3CLpro, the SARS-CoV-2 main protease, with an inhibition constant in the sub-micromolar range (Ki = 0.81 μM). Two phenylpropene analogs were also tested: the same effect was observed for estragole with a lower potency (Ki = 4.1 μM), whereas anethole was less active. The binding efficiency index of these compounds is remarkably favorable due also to their small molecular mass (MW < 165 Da). We envision that nanomolar inhibition of 3CLpro is widely accessible within the chemical space of simple natural compounds.

The SARS‐CoV‐2 main protease (Mpro): Structure, function, and emerging therapies for COVID‐19

“…Therefore, many research groups have devoted their efforts to finding anti‐CoV agents in naturally occurring compounds 48–52 . To date, a variety of marketed drugs and other structurally diverse synthetic compounds, as well as a number of natural compounds, have been found to be efficacious inhibitors of SARS‐CoV‐2 3CL pro , showing great potential for developing novel broad‐spectrum anti‐CoV agents 53–59 . Thus, this review focuses on the structural features and function of 3CL pro and recent advances in the discovery of SARS‐CoV‐2 3CL pro inhibitors, aiming to provide a SARS‐CoV‐2 3CL pro inhibitor library for medicinal chemists to design and develop more efficacious anti‐CoV agents in the future.…”

“…[48][49][50][51][52] To date, a variety of marketed drugs and other structurally diverse synthetic compounds, as well as a number of natural compounds, have been found to be efficacious inhibitors of SARS-CoV-2 3CL pro , showing great potential for developing novel broad-spectrum anti-CoV agents. [53][54][55][56][57][58][59] Thus, this review focuses on the structural features and F I G U R E 1 Phylogenetic relationships for 14 reported 3-chymotrypsin-like proteases (3CL pro s) in Nidovirus. (A) The evolutionary distances (genetic variations) of 3CL pro s are presented on branches.…”

Evaluating In Silico the Potential Health and Environmental Benefits of Houseplant Volatile Organic Compounds for an Emerging ‘Indoor Forest Bathing’ Approach

“…Although a predicted binding energy of −6.5 kcal/mol (found for β-costol) could not seem indicative of a good inhibitor, the following points should be considered: (1) a binding energy affinity/docking score of −6.0 kcal/mol is often considered as the minimum threshold for drug discovery approaches based on the molecular docking with M pro [ 35 , 36 ]; (2) since Autodock Vina software (employed in 1-Click Mcule platform) tends to underestimate the binding affinity of a ligand for its target [ 37 ], our complex could be endowed with a lower binding energy than that computed; (3) the anti-COVID-19 effects of houseplant biogenic VOCs could be synergistic, as proposed previously in the literature, for the volatile compounds isolated from the Asian evergreen plant Melaleuca cajuputi , which acted as synergistic M pro inhibitors [ 38 ]; (4) the reference compound eugenol showed in silico an affinity score for M pro even lower ( Table 1 ) [ 27 ] than our lead compound, but in vitro it was found significantly effective in the inhibition of the protease [ 32 ].…”

“…Our analysis revealed that β-costol ( 3 ) was able to form complexes with the highest affinity (with a docking score for the top-ranked pose of −6.5 kcal/mol, Table 1 and Figure 3 ) for the virus protease within all the organic compounds investigated, while sesquirosefuran (with a docking score for the top-ranked pose of −5.7 kcal/mol) showed an affinity comparable to the reference compound umbelliferone (−5.7 kcal/mol), and higher than eugenol (−5.0 kcal/mol), an experimentally validated inhibitor of M pro [ 32 ]. Interestingly, β-costol, an oxygenated sesquiterpene particularly abundant in the Helichrysum italicum , a plant with antiherpesvirus properties [ 33 ], was identified also in sea cucumber ( Holothuria atra ) extracts, which similarly showed antiviral activities against both Herpes simplex virus 1 and 2 [ 34 ].…”

“…By using molecular docking and other specific in silico methodologies utilized for vapor pressure and chemico-physical/pharmacokinetic properties prediction, we found that β-costol is an organic compound emitted in appreciable amounts by the houseplant Spathiphyllum wallisii , endowed with potential antiviral properties, as emerged by our MD calculations in SARS-CoV-2 M pro inhibition studies, together with sesquirosefuran. Interestingly, both compounds showed comparable or higher affinities for the protease with respect to eugenol, a reference compound that was found able to hamper in vitro the enzymatic activity of M pro , with an inhibition constant in the sub-micromolar range [ 32 ]. Overall, our studies suggest that the anti-COVID-19 potential of some houseplant-emitted volatile compounds, coupled with their general benefits, would help sustain the utility of indoor houseplants as biogenic volatile organic compounds emitters for boosting immunity and health protection, which can thus be exploited in ‘indoor forest bathing’ approaches, that we propose not only for private houses but also public spaces, such as offices, hospitals, and schools.…”