key: cord-1023384-c38fjpqo
authors: Rakib, Ahmed; Paul, Arkajyoti; Chy, Md. Nazim Uddin; Sami, Saad Ahmed; Baral, Sumit Kumar; Majumder, Mohuya; Tareq, Abu Montakim; Amin, Mohammad Nurul; Shahriar, Asif; Uddin, Md. Zia; Dutta, Mycal; Tallei, Trina Ekawati; Emran, Talha Bin; Simal-Gandara, Jesus
title: Biochemical and Computational Approach of Selected Phytocompounds from Tinospora crispa in the Management of COVID-19
date: 2020-08-28
journal: Molecules
DOI: 10.3390/molecules25173936
sha: 5306237650c59658a5d8fa649ba41b1276867255
doc_id: 1023384
cord_uid: c38fjpqo

A pandemic caused by the novel coronavirus (SARS-CoV-2 or COVID-19) began in December 2019 in Wuhan, China, and the number of newly reported cases continues to increase. More than 19.7 million cases have been reported globally and about 728,000 have died as of this writing (10 August 2020). Recently, it has been confirmed that the SARS-CoV-2 main protease (M(pro)) enzyme is responsible not only for viral reproduction but also impedes host immune responses. The M(pro) provides a highly favorable pharmacological target for the discovery and design of inhibitors. Currently, no specific therapies are available, and investigations into the treatment of COVID-19 are lacking. Therefore, herein, we analyzed the bioactive phytocompounds isolated by gas chromatography–mass spectroscopy (GC-MS) from Tinospora crispa as potential COVID-19 M(pro) inhibitors, using molecular docking study. Our analyses unveiled that the top nine hits might serve as potential anti-SARS-CoV-2 lead molecules, with three of them exerting biological activity and warranting further optimization and drug development to combat COVID-19.

drug chloroquine and hydroxychloroquine to combat against SARS-CoV-2 [23] [24] [25] . In addition, one study reported the antiviral activity of T. crispa along with other traditional herbs delineated antiviral activity against fish pathogenic viruses, including infectious hematopoietic necrosis virus, infectious pancreatic necrosis virus, Oncorhynchus masou virus [26] . The active components from another species of Tinospora (T. cordifolia) has been shown to represent not only antiviral activity but also protease inhibitor activity [27] . Therefore, this study rationalizes the role of screened compounds of T. crispa to combat SARS-CoV-2.

In 50 min retention time, the methanol extract of T. crispa contained a total of 309 compounds eluted between 5.0-40.0 min (Figure 1 ). Fifty-six (56) bioactive compounds were selected for this study (Table 1) .

Molecules 2020, 25 [26] . The active components from another species of Tinospora (T. cordifolia) has been shown to represent not only antiviral activity but also protease inhibitor activity [27] . Therefore, this study rationalizes the role of screened compounds of T. crispa to combat SARS-CoV-2.

In 50 min retention time, the methanol extract of T. crispa contained a total of 309 compounds eluted between 5.0-40.0 min (Figure 1 ). Fifty-six (56) bioactive compounds were selected for this study (Table 1 ). 

Using the CASTp server, we sought to identify the active pockets of the PDB protein. The area was depicted as 304.266, and the volume was 296.682. A total of 27 active site residues were identified by CASTp server, and the residues were Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, Met49, Pro52, Tyr54, Phe140, Leu141, Asn142, Gly143, Ser144, His163, His164, Met165, Glu166, Leu167, Pro168, His172, Asp187, Arg188, Gln189, Thr190, and Gln192. [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl 28 

Using the CASTp server, we sought to identify the active pockets of the PDB protein. The area was depicted as 304.266, and the volume was 296.682. A total of 27 active site residues were identified by CASTp server, and the residues were Thr25, Thr26, Leu27, His41, Cys44, Thr45, Ser46, Met49, Pro52, Tyr54, Phe140, Leu141, Asn142, Gly143, Ser144, His163, His164, Met165, Glu166, Leu167, Pro168, His172, Asp187, Arg188, Gln189, Thr190, and Gln192.

Lipinski's rule of five was followed to predict the drug-likeliness properties; the following five principles must be followed: (i) Molecular weight is not more than 500; (ii) Number of H-bond acceptors ≤ 10; (iii) Number of H-bond donors ≤ 5; (iv) Lipophilicity (Log P value) < 5; and (v) Molar refractivity between 40 to 130. Among the fifty-six compounds, twenty-three compounds fulfilled the rule of five, indicating that those compounds could be suitable for the new drug development process. The results of the ADME/T prediction of the compounds is exhibited in Table 2 . 

In this study, we are able to delineate the interaction between several isolated compounds of T. crispa with the M pro enzyme of SARS-CoV-2 (PDB ID: 6W63). The docking results demonstrated that all compounds obtained from T. crispa interacted with the SARS-CoV-2 M pro enzyme. Among these compounds, a total of seven possess higher docking scores in comparison with the others (Figure 2 ). However, some compounds exert a lower binding affinity towards the receptor (Table 3 ).

Our computational investigation shows that imidazolidin-4-one, 2-imino-1-(4-methoxy-6dimethylamino-1,3,5-triazin-2-yl) has the lowest docking score of −7.013 KJ/mol, interacting with Gly143 and Ser144 residues, respectively ( Figure 3) .

Additionally, spiro [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl exhibits a docking score of −6.369 KJ/mol, but the interaction occurs with total four amino acids (Met165, His41, Met49, Met165) through pi-alkyl stacking, unlike imidazolidin-4-one, 2-imino-1-(4-methoxy-6-dimethylamino-1,3,5-triazin-2-yl), which interacts through hydrogen bonding ( Figure 4 ). Moreover, 3.beta-Hydroxy-5-cholen-24-oic acid also tends to interact with the receptor as it has obtained a docking score of −6.251 KJ/mol. In addition, 3.beta-Hydroxy-5-cholen-24-oic acid possessed the affinity towards the receptor not only through hydrogen bonding but also pi-alkyl stacking ( Figure 5 ). On the other hand, dibutyl phthalate (−2.279 kcal/mol) possessed the lowest score (Table 3 ). In particular, our experiment also includes the calculation of binding affinity of two antiviral agents, nelfinavir and lopinavir and these aforementioned compounds exert a score of −7.596 and −8.251 Kcal/mol, respectively, withSARS-CoV-2 M pro . The molecular docking analysis results are shown in Figures 3-5 , Figures S1-S13, and Table 3 . 

Pro168, His41 (2) Arg188, His41

Molecules 2020, 25, 3936 7 of 16

In this study, we are able to delineate the interaction between several isolated compounds of T. crispa with the M pro enzyme of SARS-CoV-2 (PDB ID: 6W63). The docking results demonstrated that all compounds obtained from T. crispa interacted with the SARS-CoV-2 M pro enzyme. Among these compounds, a total of seven possess higher docking scores in comparison with the others (Figure 2 ). However, some compounds exert a lower binding affinity towards the receptor (Table 3 ). Additionally, spiro [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl exhibits a docking score of −6.369 KJ/mol, but the interaction occurs with total four amino acids (Met165, His41, Met49, Met165) through pi-alkyl stacking, unlike imidazolidin-4-one, 2-imino-1-(4-methoxy-6-dimethylamino-1,3,5triazin-2-yl), which interacts through hydrogen bonding (Figure 4) . Moreover, 3.beta-Hydroxy-5cholen-24-oic acid also tends to interact with the receptor as it has obtained a docking score of −6.251 KJ/mol. In addition, 3.beta-Hydroxy-5-cholen-24-oic acid possessed the affinity towards the receptor not only through hydrogen bonding but also pi-alkyl stacking ( Figure 5 ). On the other hand, dibutyl phthalate (−2.279 kcal/mol) possessed the lowest score (Table 3 ). In particular, our experiment also .beta-Hydroxy-5-cholen-24-oic acid ligand in the active site is shown in purple color, and ligand interacting with the residues is shown in blue color, green color illustrates the residues forming hydrogen bonds, pink color illustrates the residues with hydrophobic (pi-pi/pi-alkyl) stacking, and white color illustrates the residues with carbon-hydrogen interaction. [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl. Ligand in the active site is shown in purple color, and ligand interacting with the residues are shown in blue color, pink color illustrated the residues with hydrophobic (pi-pi/pialkyl) stacking.

Molecular docking interaction between the SARS-CoV-2 M pro and 3.beta-Hydroxy-5-cholen-24-oic acid ligand in the active site is shown in purple color, and ligand interacting with the residues is shown in blue color, green color illustrates the residues forming hydrogen bonds, pink color illustrates the residues with hydrophobic (pi-pi/pi-alkyl) stacking, and white color illustrates the residues with carbon-hydrogen interaction. Figure 5 . Molecular docking interaction between the SARS-CoV-2 M pro and 3.beta-Hydroxy-5cholen-24-oic acid ligand in the active site is shown in purple color, and ligand interacting with the residues is shown in blue color, green color illustrates the residues forming hydrogen bonds, pink color illustrates the residues with hydrophobic (pi-pi/pi-alkyl) stacking, and white color illustrates the residues with carbon-hydrogen interaction.

The selected compounds of the plant T. crispa were subjected to biological activity calculations with the help of Molinspiration software and compared with the standard drugs nelfinavir and lopinavir. The results are shown in Table 4 . 

Currently, with an acute progression rate, it has been revealed that the clinical manifestations of SARS-CoV-2 infection start with a fever with a dry cough, which continues to alveolar edema, ultimately resulting in difficulty in breathing; however, mild symptoms might not include high fever [28] [29] [30] . Nevertheless, as the death counts are rising alarmingly, the respiratory infection triggered by SARS-CoV-2 has been classified as more critical in progressing the disease state in contrast with two other coronaviruses, SARS and MERS (Middle East Respiratory Syndrome), with a large number of infections and variations that spread rapidly while exhibiting minimal symptoms in the lungs. The organism can depreciate the normal functioning of the kidney, heart, liver, and other vital organs, leading to systemic exhaustion [31] [32] [33] .

Although several kinds of research are being carried out in famous laboratories in several countries, vaccine development for disease is usually time-consuming. Despite there being plenty of experimental trials associated with COVID-19 treatment and medications, as of yet, scientists are still on the hunt for specific therapeutic drugs [34] .

About 80% of certain Asian and African countries depend on traditional medicine for their major health care needs [35] . Several endogenous receptors responsible for prominent biological functions are triggered by numerous plant-derived phytochemicals [36] . Medicinal plants are endowed with plenty of phytocompounds, and since ancient times, plant-derived compounds have been used for treatment in numerous diseases [15, 37, 38] . Diverse secondary metabolites, including alkaloids, terpenoids, lignans, glycosides, amino acids, are crucial for the growth and functioning of plants and have numerous pharmacological aspects of fighting against several abnormal conditions [39] [40] [41] . Archaically, plant-derived chemicals were considered to be a prolific fount for drug discovery. Several previous studies have already documented the essentiality of phytochemicals in numerous diseases, including cardiovascular diseases, cancer, diabetes, hepatic disorders, etc. [42] [43] [44] . Many of these phytochemicals are generally not involved in the normal functioning of plants; nonetheless, they are modified by various biochemical processes and are further required for various environmental responses, including stress, protection from ultraviolet damage [45] . The extraction of phytochemicals has recently been established as a phenomenal subject matter in lead compound identification for active pharmaceutical moieties. More detailed information about various pharmacologically active medicinal plants' crude extracts could be obtained using separation techniques, which involves the separation of active phytoconstituents [46, 47] . In this experiment, we used the GC-MS technique for qualitative analysis of the plant extracts of T. crispa and confirmed more than 300 compounds.

Recently, researchers from different parts of the world have been working extensively to find certain potential lead compounds from medicinal plants that are active against several enzymes and other proteins responsible for viral replication and growth [33, 48, 49] . In line with this, we planned in silico experiments using the isolated constituents from methanol extract of T. crispa against the SARS-CoV-2 M pro enzyme. Significantly, we have already mentioned the role of T. crispa extracts against malaria and the recent successful usage of anti-malarial drugs in combatting COVID-19, which leads the foundation for our hypothesis.

Nowadays, drug design using various bioinformatics tools has been proven as groundbreaking methods in drug discovery not only due to promptness and accuracy but also its low cost [50] . Molecular docking simulation, a form of bioinformatics analysis, signifies the binding affinities of ligand molecules with a specific receptor, in which the lower binding energy predicts the higher binding affinity [51] [52] [53] . A recent study from Yamamoto et al. has already shown that nelfinavir can inhibit SARS-CoV-2 replication in vitro [54] . Previously, another study from Yamamoto et al. reported the inhibitory effect of nelfinavir on the replication of SARS-CoV [55] . In addition, another in vitro analysis showed that lopinavir/ritonavir exhibited potential inhibitory effects on SARS-CoV-2 [56] . Hence, we selected nelfinavir and lopinavir as positive controls in the present study. In this study, our selected phytocompounds, along with two antiviral drugs, nelfinavir and lopinavir, were able to dock with the active pockets of SARS-CoV-2 M pro enzyme, which was confirmed by our analysis through CASTp web server. Despite showing lower binding affinities than nelfinavir and lopinavir, our selected compounds interacted with the active pockets of the SARS-CoV-2 M pro enzyme like the standard compounds. Additionally, imidazolidin-4-one, 2-imino-1-(4-methoxy-6-dimethylamino-1,3,5-triazin-2-yl) not only has a docking score almost the same as nelfinavir, but also, like nelfinavir, interacts with Glu166 residue through H-bonding. On the other hand, the interactions between spiro [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl and 3.beta-hydroxy-5-cholen-24-oic acid with SARS-CoV-2 M pro enzyme were found to be more than both the standard drugs. Additionally, other compounds, including androstan-17-one, 3-ethyl-3-hydroxy-, (5.alpha), camphenol, (−)-Globulol, yangambin, nordazepam, TMS derivative, and benzeneethanamine, also represented greater interaction with the abovementioned enzyme. Previously, it was found that the His41 and Cys145 residues belong to the catalytic dyads of the SARS-CoV-2 M pro [57] . In the current study, the results of the docking analysis revealed that retinal, retinol, spiro [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl, phosphonoacetic Acid, 3TMS derivative, aR-turmerone, androstan-17-one, 3-ethyl-3-hydroxy-, (5.alpha) interacted with Cys145 residue through hydrophobic interaction. Furthermore, the two standard drugs, along with most of the selected compounds, interacted with His41 residue. Like nelfinavir, benzeneethanamine also yielded interaction with His41 residue by forming hydrogen bonds. Although neither nelfinavir nor lopinavir interacted with Met49 residues, most of the targeted compounds interacted with Met49 residues, and this residue, along with His41, is crucial for substrate-binding [57] . In addition, Gly143, Ser144, His163, His164, Met165, Glu166, Leu167, Asp187, Arg188, Gln189, Thr190, Ala191, and Gln192 residues are also crucial for substrate binding in SARS-CoV-2 M pro [58, 59] . Our analysis showed that 3,4-dihydroxymandelic interacted with His163, Ser144 from the substrate-binding domain through hydrogen bonding. In addition, camphenol, possessing a greater docking score, formed a hydrogen bond with substrate-binding His164 residue. Moreover, most of the selected compounds as well as nelfinavir interacted with Met165 residue by forming a hydrophobic interaction.

Moreover, the selected compounds also followed Lipinski's rule of five for drug-likeness properties. Furthermore, the ion channel inhibitor property of spiro [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl were found more than standard compounds. Additionally, imidazolidin-4-one, 2-imino-1-(4-methoxy-6dimethylamino-1,3,5-triazin-2-yl) possessed closer kinase inhibitor attributes in comparison with the standards. In addition, 3.beta-Hydroxy-5-cholen-24-oic acid exerted greater nuclear receptor ligand than nelfinavir and lopinavir. Interestingly, both spiro [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl, 3.beta-Hydroxy-5-cholen-24-oic acid and 3.beta-Hydroxy-5-cholen-24-oic acid presented greater enzyme inhibition than either antiviral drug, whereas imidazolidin-4-one, 2-imino-1-(4-methoxy-6dimethylamino-1,3,5-triazin-2-yl) exhibited greater protease blocking activity.

The whole plant of T. crispa was collected at the mature stage from the Lawachara National Park, Moulavi Bazar, Bangladesh, in January 2018. The plant parts were cut into small pieces that were washed under tap water and then dried in the dark at 21-30 • C for 15 days. The whole plant material was ground by a mechanical grinder and passed through a size of 60 mesh sieve to obtain a fine powder that was stored in an air-tight container.

The dried T. crispa plant powder (600 g) was macerated in 4 L methanol (Merck, Darmstadt, Germany) for 15 days at room temperature with occasional shaking and stirring. Following filtration, first with a cotton plug, then with a Whatman No. 1 filter paper, the filtrate was evaporated to dryness under vacuum at 40 • C to obtain a concentrated extract (30.55 g dry weight, 5.09% w/w). The extract was preserved for further analysis.

The GC-MS analysis was evaluated using a model 7890A capillary gas chromatography along with a mass spectrometer (Agilent Technologies, Santa Clara, CA, USA). The column was a fused silica capillary column of 95% dimethyl-poly siloxane and 5% phenyl (HP-5MSI; length: 90 m, diameter: 0.250 mm and film: 0.25 µm, Merck, Darmstadt, Germany). Parameters for GC-MS detection were an injector temperature of 250 • C, and the initial oven temperature of 90 • C was gradually raised to 200 • C at a speed of 3 • C/min for 2 min and with a final increase to 280 • C at 15 • C/min for 2 min. The total GC-MS run time was 36 min, using 99.999% helium as a carrier gas, at a column flow rate of 1 mL/min. The GC to MS interface temperature was fixed at 280 • C, and an electron ionization system was set on the MS in scan mode. The mass range evaluated was 50-550 m/z, where MS quad and source temperatures were maintained at 150 • C and 230 • C, respectively. The NIST-MS Library 2009 was used to search and identify each component, and to measure the relative percentage of each compound, relative peak areas of the TIC (total ionic chromatogram) were used, with calculations performed automatically.

Potential ligand binding sites/pockets (active sites) on the 3D structure of protein were identified by the CASTp web server (http://sts.bioe.uic.edu/castp/) [60] . CASTp uses the recent algorithmic and geometrical analysis of computational chemistry for the analytical validation pockets and cavities.

The pharmacokinetic properties of all major identified compounds were evaluated using Lipinski's rule of five [61] . Lipinski stated that a compound could show drug-like behavior if it does not fail more than one of the following criteria: (i) Molecular weight is not more than 500; (ii) H-bond donors ≤ 5; (iii) H-bond acceptors ≤ 10; (iv) Lipophilicity < 5; and (v) Molar refractivity between 40 and 130. The web tool Swiss ADME was used to assess the ADME parameters of all compounds. Compounds obeying the Lipinski rule are considered as ideal drug candidates [62] .

The selected isolated compounds of T. crispa were subjected to Maestro v 10.1 (Schrödinger suite, LLC New York, NY, USA), and ligand preparation was done using the LigPrep tool. The parameters were set to neutralize at pH 7.0 ± 2.0 using Epik 2.2, and minimized by force field OPLS_2005.

3D crystal structure of SARS-CoV-2 M pro (PDB ID: 6W63) was downloaded from the Protein Data Bank and prepared using the protein preparation wizard of the Schrödinger Suite-Maestro version 10.1. Charges and bond orders were assigned, hydrogens added to heavy atoms and selenomethionines and selenocysteines converted into methionines and cysteines, respectively, followed by removing all water molecules. Using force field OPLS_2005, minimization was performed to set a maximum heavy atom RMSD to 0.30 Å.

Receptor grid generation and molecular docking experiments were performed using Glide (Schrödinger Suite-Maestro version 10.1) [63, 64] . A grid was produced for each protein using the following default parameters: van der Waals scaling factor 1.00 and charge cut-off value 0.25, subjected to the OPLS_2005 force field. A cubic box of definite dimensions centered on the centroid of the active site residues was generated for the receptor, and the box size was set to 14 Å × 14 Å × 14 Å for docking. Docking experiments were carried out using the standard precision (SP) scoring function of glide, and only the best scoring fit with docking score was noted for each ligand.

The targeted compounds were assessed for potential bioactivity by calculating their activity scores as GPCR ligands, ion channel modulators, kinase inhibitors, nuclear receptor inhibitors, and enzyme inhibitors. All the parameters were checked with the aid of the software Molinspiration (www. molinspiration.com, Nova Ulica, Slovensky Grob, Slovak Republic) [21] . Calculated drug-likeness scores of each compound were compared with each compound's specific activity and were compared with the standard drugs (nelfinavir and lopinavir).

COVID-19 created a devastating global crisis impacting thousands of people every day, taking thousands of lives and hampering the global economy. Virtual molecular docking was conducted to identify new compounds that could bind the SARS-CoV-2 M pro . The isolated compounds obtained from the methanol extract of T. crispa were investigated in silico, which concluded that some selective compounds are potentially enough to alter the activity of the SARS-CoV-2 M pro enzyme. Our analysis indicates phytochemicals from the methanolic extract of T. crispa such as imidazolidin-4-ne, 2-imino-1-(4-methoxy-6-dimethylamino-1,3,5-triazin-2-yl), spiro [4, 5] dec-6-en-1-ol, 2,6,10,10-tetramethyl, 3.betahydroxy-5-cholen-24-oic acid, androstan-17-one, 3-ethyl-3-hydroxy-(5.alpha), camphenol, (−)-Globulol, yangambin, nordazepam, TMS derivative, benzeneethanamine have a better binding affinity to M pro of SARS-CoV-2 compared to nelfinavir and lopinavir. Further research and development will pave the way for identifying possible SARS-CoV-2 M pro inhibitors. We anticipate that the insights obtained in this study can be useful for the potential discovery and development of new natural anti-COVID-19 therapeutic agents. 

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The authors declare no conflict of interest.