INTRODUCTION
The outbreak of coronavirus disease-19 (COVID-19) has now become a significant global health issue. Until the November 2020 update, more than 50 million people have become infected, and over a million have died due to this pandemic (https://covid19.who.int/). This number is still growing day by day, describing the war against COVID-19 as continued. Although several companies already announced that they have proposed vaccine candidates entering the final phase of clinical trials, complementary medicine and dietary intervention still needed to prevent the severity of infected people and prevent healthy people from getting infected (Di Matteo et al., 2020; Panyod et al., 2020). Therefore, exploring the proper diet for patients or healthy people to help against COVID-19 infection becomes essential.
Thwarting severe acute respiratory syndrome-coronavirus (SARS-CoV-2) attachment and replication have become the main target for combating COVID-19 (Jha et al., 2020; McKee et al., 2020). Several proteins from SARS-CoV-2 have been modeled and appropriately studied as a target to decrease the number of positive cases (Dai et al., 2020; Xia et al., 2020; Zhang et al., 2020a). Spike protein is the primary key for SARS-CoV-2 to enter the host’s cell, consisting of unique parts called heptad repeat 1 (HR1) and HR2 inside the receptor binding domain (RBD) for performing membrane fusion after attachment (Bosch et al., 2004; Walls et al., 2020; Xia et al., 2020). With this critical role, HR1 and HR2 have been proposed as the main targets to evade viral entry and infection (Xia et al., 2020). Another protein called main protease (MPro) has also become the right candidate due to its vital role in the viral replication and transcription (Hilgenfeld, 2014). Therefore, several studies also used MPro as a target to inhibit the severity of the COVID-19 infection (Ahkam et al., 2020; Dai et al., 2020; Jin et al., 2020; Joshi et al., 2020).
Another perspective to support a patient’s survival is suppressing massive inflammation in lung tissue (Heck et al., 2020; Zhang et al., 2020b). This inflammation, known as cytokine storms, occurs through the deregulation of the immune response, leading to the disturbance of tissue homeostasis and severe organ damage (Ragab et al., 2020; Soy et al., 2020). Subsequently, injury in the lung tissue gives rise to breathing difficulties and speeds up the patient’s death (Acosta and Singer, 2020; Lin et al., 2020). NF-κB, a kind of transcription factor which controls several cytokines involved in cytokine storms like interleukin- (IL-) 1 and IL-6, has a good starting point to diminish the hyperinflammation (Catanzaro et al., 2020; Conti et al., 2020; Soy et al., 2020). Previously, suppressing NF-κB could increase the survival rate after coronavirus infection (DeDiego et al., 2014). Thus, targeting this transcription factor has a reasonable probability of improving patient survival.
Legumes have been a good source of nutrition for years. However, masses of legume species are still underutilized as nutritious food. One of the rarely used legumes is Dolichos lablab (DL) (Minde et al., 2020). DL not only has a high nutritional content but also has innumerable natural compounds with numerous biological activities. Several bioactive compounds were reported to be contained in DL, including gallic acid, 4-hydroxy-3-methoxybenoic acid, p-coumaric acid, ferulic acid, cinnamic acid, catechin, and rutin. Also, saturated and unsaturated fatty acids, terpenoids, and steroids were found as a constituent inside DL beans (Baba et al., 1983; Bahtiar et al., 2017; Habib et al., 2017b; Yoshikawa et al., 1998). Previously, DL was explored for its antioxidant, antidiabetic, antimicrobial, and even anti-inflammatory properties (Habib et al., 2017a; Naeem et al., 2020; Rahman and Akhter, 2018; Yin et al., 2018). With those various health benefits, DL is a promising candidate for dietary supplementation to avoid COVID-19 infection.
MATERIAL AND METHOD
Phytochemical content screening
Thermo Scientific Dionex Ultimate 3,000 RSLCnano liquid chromatography (LC) coupled with Thermo Scientific Q Exactive Mass Spectrometry (MS) was run to identify the phytochemical content inside the methanolic extract of DL. Hypersil GOLD aQ 50 × 1 mm × 1.9 μ particle size was installed in the LC instrument as stationary phase, while the mobile phase consists of solvent A (0.1% formic acid in water) and solvent B (0.1% formic acid in acetonitrile). The LC was operated under the following conditions: flow rate of 40 μl/minutes, 30 minutes run time, and 30°C column temperature. The obtained data were analyzed using Compound Discoverer with mzCloud in the MS/MS Library. Compound with mzCloud best matched a score higher than 80, and then directed for further analysis.
Ligand and protein structures retrieval
The compounds from liquid chromatography–high-resolution mass spectrometry (LC–HRMS) analysis were used as the ligand. The three-dimensional (3D) structure of the ligands was assessed through the PubChem database (Supplementary File 1). The protein’s 3D structures were retrieved from Protein Data Bank (https://www.rcsb.org/), i.e., MPro (PDB ID: 6M2N), HR complex (6LXT), and NF-κB (1SVC) according to previous studies (Muzaffer et al., 2017; Su et al., 2020; Xia et al., 2020).
Molecular docking
Water molecules and native ligand from the 3D protein structures were removed using Discovery Studio 16. Energy minimization of the ligand structures was prepared using Open Babel integrated into PyRx 8.0 (O’Boyle et al., 2011). All compounds from LC-HRMS were screened using molecular docking to predict its interaction against protein targets. Protein–ligand docking was carried out using AutoDock Vina integrated into PyRx 8.0 (Dallakyan and Olson, 2015; Trott and Olson, 2010) with a maximum grid-size setting. HEX 8.0 was run for protein–protein docking using the default setting and operated under Shape + DARS correlation type (Ritchie and Kemp, 2000). As a comparison, hydroxychloroquine [HCQ, compound identity number (CID): 3,652] (Procacci et al., 2020) and 4,6-dichloro-N-phenyl-1,3,5-triazine-2-amine (NI241, CID: 167,66) (Kobayashi et al., 2016) were employed as a control inhibitor for MPro and NF- κB, respectively.
Data analysis
The protein–ligand complex, which has a binding energy lower than −7 kcal/mol, was directed for further analysis. Interacted residues in each protein–ligand complex and structure conformation were analyzed and visualized using Discovery Studio. The protein structure alignment was executed using PyMOL 2.3.2 with the RMSD value determined as a structural difference among aligned proteins. The alignment was achieved by setting the HR1–HR2 complex as a reference structure.
Prediction of drug-likeness properties
Drug-likeness properties were analyzed according to Lipinski’s Rule of 5 (LRO5) (Lipinski, 2004). Drug resemblance properties were determined using the SwissADME physicochemical properties (Daina et al., 2017), including molecular weight (MW), LogP value, the number of H-bond donors, H-bond acceptor, rotatable bond, and total polar surface area (TPSA).
RESULT AND DISCUSSION
According to the binding affinity, 16 compounds were identified to have biological activities against SARS-CoV-2 infection and inflammation; five of them have a binding energy lower than −7 kcal/mol consistently in every target protein. 19-Nortestosterone, mesterolone, oleanolic acid, rutin, and ursolic acid are the compounds that have a low binding energy in MPro, HR1, and NF-κB. MPro is the protein that can interact with more compounds tested with a binding energy lower than or equal to −7 kcal/mol. Based on the binding affinity lower than or equal to −7 kcal/mol, seven compounds could interact with HR1, while six compounds were docked with NF-κB (Table 1).
19-Norandrostenedione, 19-nortestosterone, galaxolidone, mesterolone, oleanolic acid, rutin, and ursolic acid are the compounds that have good affinity to HR1. Attachment of these compounds could alter the HR1–HR2 binding motif represented by declining the HR complex’s binding energy after being bonded with those compounds compared to the HR complex without ligand (Fig. 1a). Among the seven compounds that have an excellent affinity to HR1, rutin could modify the HR1–HR2 interaction. This was described by the RMSD value of the HR complex with rutin inside compared to the HR complex alone, which has a greater value than other complexes (Fig. 1b). Interaction of HR1–HR2 to form the helix bundle is the crucial step for SARS-CoV-2 membrane fusion (Liu et al., 2004; Ou et al., 2020). Altering the helix bundle formation has been studied to prevent viral entrys (Xia et al., 2020), suggesting that 19-norandrostenedione, 19-nortestosterone, galaxolidone, mesterolone, oleanolic acid, ursolic acid, and in particular rutin have an excellent potency to inhibit viral infection.
 | Table 1. Phytochemical with binding energy less than or equal to −7 kcal/mol during screening process using molecular docking. [Click here to view] |
MPro is the target protein with plenty of interacted compounds. Compared to HCQ as control, all the compounds have a lower binding energy. Each compound has its favorable binding region, presented by structural visualization (Figure 2) or interacted residues between the ligand molecule and MPro. Among those compounds, only daidzein and (9cis)-retinal have an interaction with catalytic residues of MPro at HIS:41. HCQ did not show any interaction with the catalytic residues (Supplementary File 2). HIS:41 and CYS:145 have been known as essential residues during MPro enzymatic activity (Tahir ul Qamar et al., 2020). Inhibiting these residues has a promising effect on preventing virus replication and prevent viral spreading throughout the tissues (Ahkam et al., 2020; Gyebi et al., 2020; Hosseini-Zare et al., 2020; Tahir ul Qamar et al., 2020).
NF-κB is the transcription factor of several proteins related to infection response, including cytokines related to defense mechanisms (Hayden et al., 2006; Schmitz et al., 2014). At this critical condition, cytokine storms are the main factors that contribute to lung damage due to the overexpression of proinflammatory cytokines (Lin et al., 2020; Soy et al., 2020). Thus, targeting NF-κB as the main transcription factor for suppressing those cytokines’ hyperexpression could play a vital role in augmenting patient survival (Catanzaro et al., 2020). From the docking result, six compounds could interact with NF-κB at -7 kcal/mol or lower. Although the ligands did not bind with the vital residues involved in NF-κB DNA-binding site, several interacted amino acids take place adjacent to these binding sites (Figure 3), suggesting their potentials as NF-κB inhibitors (Müller et al., 1995). Targeting DNA-binding sites of NF-κB has been employed to preclude chronic inflammation (Gilmore and Herscovitch, 2006; Gupta et al., 2010). Therefore, the presence of those compounds in the NF-κB DNA-binding domain could reduce hyperinflammation by altering the proinflammatory cytokines’ transcription process.
 | Figure 1. Structural orientation and binding energy of the HR complex after being bound with phytochemical ligands (A) and structural alignment of HR complex before and after being bound with phytochemical ligands (B). The blue ribbons in Figure A represent the HR protein complex, while the yellow spheres describe the phytochemical ligand. In Figure B, the blue ribbons represent the initial form of the HR complex without the ligand, while the red ribbons represent the HR complex structure after being bound with the phytochemical ligands. [Click here to view] |
 | Figure 2. Structural visualization of MPro after being bound with its inhibitor and phytochemical ligands: HCQ (A), (9cis)-retinal (B), 19-norandrostenedione (C), 19-nortestosterone (D), 3-hydroxy-3,5,5-trimethyl-4-(3-oxo-1-buten-1-ylidene)cyclohexyl β-D-glucopyranoside (E), benzoic acid (F), daidzein (G), dimethomorph (H), galaxolidone (I), ilicic acid (J), isoquercetin (K), mesterolone (L), oleanolic acid (M), psilostachyin B (N), rutin (O), and ursolic acid (P). [Click here to view] |
 | Table 2. Physicochemical properties of screened phytochemicals according to SwissADME measurement. [Click here to view] |
 | Figure 3. Structural visualization of NF-κB after being bound with DNA (A), NI241 (B), 19-nortestosterone (C), mesterolone (D), oleanolic acid (E), psilostachyin B (F), rutin (G), and ursolic acid (H). [Click here to view] |
Several criteria have been developed by Lipinski for a small molecule to have good oral bioavailability, permeability, and flexibility (Lipinski, 2004). The oral bioavailability of small molecules is determined by several criteria, including MW, LogP value, the number of hydrogen bond donors, and acceptor less than 500 g/mol, 5, 5, and 10, respectively (Lipinski, 2004). Also, a molecule with a TPSA value equal or less than 140 Šwill carry out good permeability, while the number of rotatable bonds less than 10 represents molecule flexibility (Chagas et al., 2018). Hence, SwissADME was employed to do the calculations related to LRO5. All of the analyzed compounds, except for rutin and (9cis)-retinal, have no violations of the MWmolecular weight, LogP value, H-bond donor, H-bond acceptor, rotatable bonds, and TPSA criteria. Rutin had a low oral bioavailability and permeability with 610.52 g/mol of MW, 10 of H-bond donor, 16 of H-bond acceptor, and 269.43 Ų TPSA value. (9cis)-Retinal is also not better than rutin in terms of oral bioavailability and permeability with 8 of H-bond donor, 12 of H-bond acceptor, and 210.51 Ų TPSA value (Table 2).
CONCLUSION
There are seven herbal compounds from DL, which have good potential as a preventive or complementary agent for COVID-19 treatment based on the constant binding energy lower or equal to -7 kcal/mol with MPro or HR1. However, daidzein has better potency as an MPro inhibitor, while rutin showed a worthy effect to prevent viral-host fusion by modifying the HR complex structure orientation. As anti-inflammatory candidates, 19-nortestosterone, mesterolone, oleanolic acid, and ursolic acid have a satisfactory result as NF-κB inhibitors. Lastly, all compounds with a binding energy lower than or equal to −7 kcal/mol, except for (9cis)-retinal and rutin, have good oral bioavailability, permeability, and flexibility.
ACKNOWLEDGMENTS
The authors acknowledge the Ministry of Research, Technology, and Higher Indonesia, the Republic of Indonesia, for funding this research under Grant no. 229/SP2H/LT/DRPM/2019.
AUTHOR CONTRIBUTIONS
All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the international committee of medical journal editors (ICMJE) requirements/guidelines.
CONFLICTS OF INTEREST
The authors report no financial or any other conflicts of interest in this work.
ETHICAL APPROVALS
This study does not involve experiments on animals or human subjects.
PUBLISHER’S NOTE
This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.
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