key: cord-0915813-2ju17dom
authors: Sisakht, Mohsen; Mahmoodzadeh, Amir; Darabian, Maryam
title: Plant‐derived chemicals as potential inhibitors of SARS‐CoV‐2 main protease (6LU7), a virtual screening study
date: 2021-03-23
journal: Phytother Res
DOI: 10.1002/ptr.7041
sha: 0afd00b9edaebb224b4a7866ae9ffda8210893c7
doc_id: 915813
cord_uid: 2ju17dom

SARS‐CoV‐2 has caused millions of infections and more than 700,000 deaths. Taking the urgent need to find new therapeutics for coronavirus disease 2019 (COVID‐19), a dataset of plant‐based natural compounds was selected for the screening of antiviral activity. The viral 3‐chymotrypsin‐like cysteine protease (Mpro, 3CLpro) was selected as the target. Molecular docking was performed on 2,845 phytochemicals to estimate the spatial affinity for the active sites of the enzyme. The ADMET screening was used for the pharmacological and physicochemical properties of the hit compounds. Nelfinavir and Lopinavir were used as control for binding energy comparison. The top 10 hits, based on the binding energy (Kcal/mol), were Ginkgolide M (−11.2), Mezerein (−11), Tubocurarine (−10.9), Gnidicin (−10.4), Glycobismine A (−10.4), Sciadopitysin Z‐10.2), Gnididin (−9.2), Glycobismine A (−10.4), Sciadopitysin (−10.2), Gnididin (−9.20, Emetine (−8.7), Vitexin (−8.3), Calophyllolide (−8.3), and 6‐(3,3‐Dimethylallyl)galangin (−7.9). The binding energy for nelfinavir and lopinavir were − 9.1 and − 8.4, respectively. Interestingly, some of these natural products were previously shown to possess antiviral properties against various viruses, such as HIV, Zika, and Ebola viruses. Herein, we suggest several phytochemicals as the inhibitors of the main protease of SARS‐CoV‐2 that could be used in the fight against COVID‐19.

Whole-genome analysis has shown that SARS-CoV-2 and SARS belong to clade b of the genus Beta-coronavirus, and share 82% sequence homology (Chan et al., 2020; Hasan et al., 2020) .

Upon transcription of the SARS-Cov-2, an 800 kDa polypeptide is produced, subsequently is proteolyzed and generates non-structural proteins. The proteolytic processing is mediated by papain-like protease (PLpro) , and 3-chymotrypsin-like protease (3CLpro, also called Mpro); both are cysteine proteases. There is a high structural similarity for this protein among SARS-CoV and SARS-CoV-2, 96% sequence identity for 3CLpro (Anand, Ziebuhr, Wadhwani, Mesters, & Hilgenfeld, 2003; Zhang et al., 2020) . The proteolytic activity of 3CLpro is vital for the production of structural and nonstructural proteins, replication, and packaging of the new virus. This protein was successfully crystalized, and very soon being investigated as a potential target in drug design studies .

The amino acids found in the active site of the enzyme are THR24, THR26, PHE140, ASN142, GLY143, CYS145, IS163, HIS164, GLU166, HIS172 (Khaerunnisa et al., 2020) . Earlier efforts to target SARS-CoV resulted in the identification of several 3CLpro inhibitors targeting the catalytic dyad of the protein defined by His41 and Cys145 residues (Paasche et al., 2014) . Here, we used a diverse library of phytochemicals, based on the antiviral, other health benefits, and less adverse effect, for finding possible inhibitors of 3CLpro. The molecular docking and Lipinski Rule of Five were calculated. The binding energy of the compound to the active site of the enzyme was compared to lopinavir/nelfinavir, since these are currently used in the clinic as one of the possible therapies of COVID-19 (Arabi et al., 2020; Hung et al., 2020) .

Several studies have shown the therapeutic value of targeting of 3CLpro in SARS-CoV and MERS-CoV (Liang et al., 2018) . 3CLpro not only is involved in the life cycle of the virus but also has interactions with the host's immune system. It suppresses host's immune response through deubiquitinating of interferon regulatory factor 3 (IRF3), and inactivation of nuclear factor κ-light-chain-enhancer (NF-κB), in the activated B cells (Baez-Santos, St John, & Mesecar, 2015) . So, it seems that inhibitors of 3CLpro may benefit the host through inhibition of viral replication and suppressing its interaction with host's immune system . Several protease inhibitors have been introduced in the treatment of COVID-19. For example, lopinavir, as an inhibitor of HIV virus inhibitor, has shown that completely recover signs of COVID-19 related pneumonia Wu, Liu, et al., 2020) . The critical role of the enzyme in the management of the viral life cycle, and its uniqueness, no similar enzyme is found in the host cells, have made 3CLpro the most attractive target for the treatment of COVID-19.

The genome of SARS-CoV-2, positive-sense, single-stranded RNA, encodes non-structural proteins (such as 3-chymotrypsin-like protease, papain-like protease, helicase, and RNA-dependent RNA polymerase

[RdRp]), structural proteins (such as spike glycoprotein) and accessory proteins (Li & De Clercq, 2020) . Based on the previous studies, three distinct targets could be regarded as the potential targets ineffectively combat CoVs, including Angiotensin-converting enzyme II (ACE2) entry receptor, the RdRp and the 3CLpro proteins (Adhikari et al., 2020) . Inhibitors against ACE2 is probably are associated with severe side effects due to the possible interference with the host's physiological conditions (Han, Penn-Nicholson, & Cho, 2006) . Also, RdRp inhibitors are associated with low potency and specificity (Zumla, Chan, Azhar, Hui, & Yuen, 2016) . The 3CLpro is crucial in the proteolytic maturation of the virus and has been considered as a potential key target to halt the viral life cycle (Liang et al., 2018) . 3CLpro is the main protease found in SARS-CoV 2, which has been structured and repositioned in PDB (6LU7) and can be accessed by the public in February 2020 . The amino acids found in the active site of the enzyme are THR24, THR26, PHE140, ASN142, GLY143, CYS145, IS163, HIS164, GLU166, HIS172 (Khaerunnisa et al., 2020) . Earlier efforts to target SARS-CoV resulted in identifying of several 3CLpro inhibitors targeting the catalytic dyad of the protein defined by His41 and Cys145 residues (Paasche et al., 2014) .

It has shown that nelfinavir can inhibit CoVs in vivo and in vitro models (IC50 = 0.048 μM) (Hsieh et al., 2010) . Fortunately, specific inhibitors against 3CLpro, such as lopinavir/nelfinavir, have led to promising results (Lin, Shen, He, Li, & Guo, 2020) . Taking the promising outcomes of previous studies, the availability of X-ray crystal structure of the enzyme and crucial role in the viral life cycle, 3CLpro could be regarded as the most promising drug target in the fight against COVID-19 (Park et al., 2016) . So, in this study, we selected lopinavir/nelfinavir, as the inhibitors of 3CLpro and docked them as controls.

Plant-derived compounds, also known as phytochemicals, are secondary metabolites in the plants, involved in plant's defense system against free radicals, viruses, bacteria, and fungi (Barbieri et al., 2017) .

These bioactive compounds possess various health benefits, such as antioxidant, antiinflammatory, cytoprotective, anticancer, antimicrobial, and antiviral properties (Barbieri et al., 2017; Chikhale et al., 2020; Islam et al., 2020; Oguntibeju, Aboua, & Omodanisi, 2020) . It has been reported that antiviral properties of phytochemicals are exerted through a wide range of mechanisms, including inhibition of the DNA\RNA metabolism or obstructing viral entry (Ben-Shabat, Yarmolinsky, Porat, & Dahan, 2020; Liu & Du, 2012) . It has shown that the plant-based compounds have promising anti-SARS-CoV-2 properties, and their effective antiviral potential and minimum side effects have opened new opportunities (Khaerunnisa et al., 2020; Ubani et al., 2020) . For example, several phenolic compounds extracted from Isatis indigotica have shown to have a remarkable inhibitory effect on 3CLpro with IC50 values, ranged from 8.3 to 1,210 μM (Lin et al., 2005) .

This study aims at screening a set of phytochemicals to find potent inhibitors of the main protease of SARS-CoV-2, as a possible approach in the fight against COVID-19. Molecular docking was performed using two AutoDock 4 and Vina software on a set of 2,223 phytochemicals, and the spatial affinity for the active sites and interactions with active site residues were studied.

We used a dataset of compounds covering different groups of phytochemicals, obtained from KEGG "Phytochemical Compounds" (http:// www.genome.jp/kegg-bin/get_htext?br08003.keg). The resulting library was diverse, representing over 2,000 scaffolds. The library included alkaloids (714 compounds), amino acid-related compounds (104), fatty acids-related compounds (37), flavonoids (478), phenylpropanoids (189), polyketides (136), shikimate/acetate-malonate pathway derived compounds (45), terpenoids (101), and others (41), totally 2,845. 3D crystal structure of SARS-CoV-2 3clpro/Mpro (PDB ID; 6LU7) was retrieved from protein data bank (PDB; (https://www. rcsb.org/), in pdb format. The native inhibitor for 3CLpro n-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-n1-((1r,2z)-4-(benzyloxy)-4-oxo-1-(31) but-2-enyl)-l-leucinamide was docked as a potential noncovalent inhibitor of SARS-CoV 3CLpro (Khaerunnisa et al., 2020) . Furthermore, specific inhibitors against 3CLpro, including Lopinavir and Nelfinavir were used for comparison .

The preparation of 3CLpro structure for the docking process was included water molecules and the co-crystal inhibitor exclusion. MGLTOOLS 1.5.6 (Morris, Huey, & Olson, 2008) was applied for converting the structure to PDBQT format and adding gasteiger partial charges. 

AutoDock4 (AD4) (release 4.2.6) (Morris et al., 2009 ) was used for the validation molecular docking result of AutoDock Vina. AutoGrid (Morris et al., 2009 ) program supplied with AD4 was used for the preparation of grid maps. The grid box size was set at 40 Å for x, y, and z dimensions.

The spacing between the grid points was 1.0 Å. The grid center was established at −11.993, 15.425, and 65.951 Å for x, y, and z, respectively.

The Lamarckian Genetic Algorithm (LGA) was chosen to search for the best conformers. During the docking process, a maximum of 10 conformers was considered for each ligand. All the docking processes were performed with the default parameters of AD4. Population size was set to 150, the maximum number of evaluations 2,500,000, the maximum number of generations 27,000, maximum number of top individuals that automatically survived 1, gene mutation rate 0.02 and crossover rate 0.8.

Drug-like properties of 2,845 phytochemicals were calculated using Lipinski's rule of five, which proposes that molecules with poor permeation and oral absorption have molecular weights ≤500, Consensus logP ≤5, equal to five or less than 5 hydrogen-bond donors, and equal to 10 or less than 10 acceptor groups (Gimenez, Santos, Ferrarini, & Fernandes, 2010; Lipinski, Lombardo, Dominy, & Feeney, 1997) . Adherence with Lipinski's rule of five was calculated using SWISSADME prediction (http://www.swissadme.ch/), 2,223 phytochemicals were approved for drug-like properties.

In this study, a comprehensive compounds library, including 2,845 phytochemicals, was obtained from KEGG "Phytochemical Compounds." The library included a wide range of phytochemicals, such as alkaloids, flavonoids, and phenylpropanoids. A total of 2,845 phytochemical compounds were considered for docking analysis using AutoDock Vina, and validated using AutoDock4. Finally, the best 10 compounds were filtered using binding energy. These compounds The 10 lead compounds and their binding energy, corresponding 2D structure, the interacting residues, and the hydrogen bonding are presented in Tables 1 and 2. This part of the study indicates remarkable binding affinities for the studied phytochemicals, compared to nelfinavir and lopinavir, −9.1 and −8.4, respectively.

Furthermore, the best 10 phytochemicals obtained by AutoDock Vina and AutoDock 4 with their corresponding docking scores and the interacting residues are presented in Table 3 ; catalytic dyad residues (His41 and Cys145) are shown in bold. Binding energy distribution for AD4 and Vina is shown in Figure 1 . A comparison of the predicted binding energies from both programs is shown in Figure 2 The interacting of the binding residues of 3CLpro with the top the compounds, native inhibitor, and lopinavir and nelfinavir are depicted in Figure 1 and Table 3 . As it is shown in Table 2 Mezerein, as the second top potent compound in our study, is a toxic diterpene ester found in the sap of Daphne mezereum and related plants. Mezerein is highly liposoluble and can cause vomiting, diarrhea, and burning of the mouth (Nelson, Shih, Balick, & Lampe, 2007) . Tubocurarine is also known for its toxic effects. So, apparently these cannot be regarded as therapeutic due to cytotoxic effects. However, gnidicin as the fourth top compound is previously shown to be an antiviral compound. Vidal et al. showed that this compound, as one of the active ingredients of Daphne Gnidium, exhibits strong antiretroviral activity, CXCR4-tropic HIV-1 strain NL4-3 or the CCR5-tropic HIV-1 strain NLAD87, and absence of cytotoxicity (Vidal et al., 2012) . Also, there are reports indicating the health benefits of other studied compounds, such as anti-Pneumocystis Carinii activity of Glycobismine A (Queener et al., 1991) and neuroprotection and antiinflammatory effects of Sciadopitysin (Choi, Suh, Rhee, & Kim, 2014) . Furthermore, it has shown that emetine, a natural alkaloid, strongly reduced the production of RNA and DNA viruses without generating drug-resistant virus variants (Khandelwal et al., 2017) . Similarly, ementin is able to inhibit Zika and Ebola virus infections through two molecular mechanisms; inhibiting viral replication and decreasing viral entry (Yang et al., 2018) . Ementin also inhibits HIV-1 replication by interfering with reverse transcriptase activity (Valadão et al., 2015) .

Vitexin, isolated from Trollius chinensis Bunge, has shown to have antiviral activity against parainfluenza type 3. The flower of this plant is used for treating upper respiratory infections, pharyngitis, tonsillitis, and bronchitis in Chinese folk medicine (Li, Ma, Yang, Ye, & But, 2002) . Furthermore, vitexin exhibits significant antiviral activity (EC50 = 35 ± 2.7 and 18 ± 3.3 μg/ml against HAV-H10 and HSV-1 virus, respectively) (Fahmy et al., 2020) . Calophyllolide, isolated from Calophyllum inophyllum, is shown to be a strong anti-HIV-1 compound (Laure, Raharivelomanana, Butaud, Bianchini, & Gaydou, 2008) .

Galangin is a strong antiviral compound against herpes simplex virus type 1 (HSV-1) and coxsackie B virus type 1 (Cox B1) (Meyer, Afolayan, Taylor, & Erasmus, 1997) . Details of the selected compounds with previously proven antiviral activity are summarized in Table 4 .

Ginkgo biloba and its derivatives, such as Ginkgolide M are widely used in traditional Chinese medicine. Nowadays, the leaf extracts are being sold as phytomedicine in Europe and as a dietary supplement worldwide (Strømgaard & Nakanishi, 2004) . Several health benefits have been reported for this phytomedicine, including improvement of memory, neuroprotection, increased blood circulation, as well as beneficial effects to sufferers of Alzheimer's disease (Mohammad Nabavi et al., 2015; Polich & Gloria, 2001; Zimmermann, Colciaghi, Cattabeni, & Di, 2002) . cysteine proteases family. Furthermore, HIV protease inhibitors specifically fit to C2 symmetry in the catalytic site of the HIV protease dimer, but this C2-symmetric pocket is absent in coronavirus proteases (Pandey et al., 2020) . As chymotrypsin and other proteins with similar 3D folding are serine proteases, it raised the hypothesis that 3CLpro was originally a chymotrypsin-like serine protease that later evolved into a cysteine protease (Shan, Li, & Xu, 2004) . That a chymotrypsin-fold protease may be a target for HIV-protease inhibitors is supported by in vitro experiments of independent groups, showing that HIV-protease inhibitors also inhibit chymotrypsin-like components of the mammalian proteasome (Piccinini et al., 2002) .

Moreover, it has shown that SARS-CoV2 3CLpro protease has a striking three-dimensional with hepatitis C virus (HCV) NS3/4A protease, particularly in the arrangement of key active site residues (Bafna et al., 2020) . This could be due to convergent evolution, in which different structural topologies create similar binding pockets.

For example, Cus145 and His41 create catalytic dyad in 3Cl pro; however, Cys172 and His44 sidechains in the three-dimensional structure of hepatitis A virus 3Cpro protease.

The possible cytotoxic effects of the studied compounds may also be considered as a limitation in the clinical use of the. We have tried to do a literature review to find reports indicating possible toxic effects of the studied compounds. It has shown that Gnidicin and other active components of Daphne gnidium have high antiviral activity with absence of cytotoxicity at even high concentrations, 50 μM (Vidal et al., 2012) . It has shown that glycobismine A is a potent antimalarial agent that are comparable to or greater than that of chloroquine diphosphate, no cytotoxic effect was found for this compound (Fujioka, Nishiyama, Furukawa, & Kumada, 1989) . Sciadopitysin is a strong anti-oxidant, neuroprotective and anti-inflammatory bioflavonoid, and no cytotoxic effect has been reported for it at concentrations up to 10 μM (Cao et al., 2017; Choi et al., 2014) . Vitexin is a cytoprotective compound, acting through a wide range of protective mechanism. It has shown that cyto-and neuroprotective properties of vitexin is exerted through decrease of intracellular Ca +2 , inhibition of inflammation, block the production of free radicals as well as effect on the gene expression level of the cellular antioxidant system ( 

Herpes simplex virus type 1 (HSV-1) and coxsackie B virus type 1 (cox B1) Meyer et al. (1997) CoVs. The antiviral mechanism of the mentioned compounds is mainly mediated through inhibition of the main protease, as a proven drug discovery target, of the coronaviruses as well as inhibition of the ion channels (Schwarz et al., 2014) . Our effort to target the main protease of the SARS-CoV2 yielded promising results. We performed molecular docking on more than 2000 phytochemicals, and we found 10 novel compounds to serve as inhibitors of 3CLpro protein. The selected natural products showed stronger binding energies than nelfinavir and lopinavir. Interestingly, these compounds were previously shown to possess antiviral properties. We, therefore, anticipate that the insights given in the current study could be regarded valuable towards the exploration and development of new therapies against COVID-19 by efficiently targeting and inhibiting the catalytic function of the main protease of the virus. This study warrants further experimental work for finding useful candidates for COVID-19 drug therapy.

Data available on request from the authors.

Amir Mahmoodzadeh https://orcid.org/0000-0002-0523-8152

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