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Article

In Silico Studies of Some Isoflavonoids as Potential Candidates against COVID-19 Targeting Human ACE2 (hACE2) and Viral Main Protease (Mpro)

by
Mohamed S. Alesawy
1,*,
Abdallah E. Abdallah
1,
Mohammed S. Taghour
1,
Eslam B. Elkaeed
2,3,
Ibrahim H. Eissa
1,* and
Ahmed M. Metwaly
4
1
Medicinal Pharmaceutical Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
2
Department of Pharmaceutical Sciences, College of Pharmacy, AlMaarefa University, Ad Diriyah, Riyadh 13713, Saudi Arabia
3
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
4
Department of Pharmacognosy and Medicinal Plants, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo 11884, Egypt
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(9), 2806; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092806
Submission received: 22 March 2021 / Revised: 10 April 2021 / Accepted: 25 April 2021 / Published: 10 May 2021
(This article belongs to the Special Issue Molecular Modeling: Advancements and Applications)
Browse Figures
Versions Notes

Abstract

:
The Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the “COVID-19” disease that has been declared by WHO as a global emergency. The pandemic, which emerged in China and widespread all over the world, has no specific treatment till now. The reported antiviral activities of isoflavonoids encouraged us to find out its in silico anti-SARS-CoV-2 activity. In this work, molecular docking studies were carried out to investigate the interaction of fifty-nine isoflavonoids against hACE2 and viral Mpro. Several other in silico studies including physicochemical properties, ADMET and toxicity have been preceded. The results revealed that the examined isoflavonoids bound perfectly the hACE-2 with free binding energies ranging from −24.02 to −39.33 kcal mol−1, compared to the co-crystallized ligand (−21.39 kcal mol–1). Furthermore, such compounds bound the Mpro with unique binding modes showing free binding energies ranging from −32.19 to −50.79 kcal mol–1, comparing to the co-crystallized ligand (binding energy = −62.84 kcal mol–1). Compounds 33 and 56 showed the most acceptable affinities against hACE2. Compounds 30 and 53 showed the best docking results against Mpro. In silico ADMET studies suggest that most compounds possess drug-likeness properties.

Graphical Abstract

1. Introduction

In December 2019, an outbreak of severe pneumonia caused by the novel severe SARS-CoV-2 originated in Wuhan, China. The infection spread all over the world causing coronavirus disease (COVID-19) [1,2]. By October 2020, COVID-19 caused more than 33 million infections and more than 1 million deaths according to the WHO [3]. Unfortunately, till now there is no specific antiviral drug available for the treatment of COVID-19-infected people. However, some drugs such as remdesivir showed modest activity through decreasing the mortality rate and treatment time [4].
Mpro is an essential non-structural chymotrypsin-like cysteine proteases enzyme for the replication of coronavirus. It works on two large polyproteins (PP1a and PP1ab) releasing 16 essential non-structural proteins (NSPs 1-16) [5,6].
Angiotensin-converting enzyme (ACE-2) is a crucial enzyme in the renin-angiotensin system. It is a significant target for antihypertensive drugs [7]. It is primarily expressed in renal tubular epithelium and vascular endothelium cells [8]. It was also reported to be expressed in lungs and GIT, tissues shown to harbor SARS-CoV [9,10]. The binding of SARS-CoV-2 to ACE-2 receptors was reported to play a pivotal role in the first binding step at the cellular membrane [11]. SARS-CoV-2 entry was mediated by its transmembrane spike glycoprotein [12]. ACE-2 was identified as the cellular receptor to which spike glycoprotein of SARS-CoV-2 binds [13]. Several reports confirmed that the SARS-CoV-2 infects human cells through ACE-2 receptor [11,14]. Furthermore, it was found that the overexpression of ACE-2 in a living cell facilitates virus entry [15].
Natural secondary metabolites are a major source of anti-infective drugs. These metabolites could be originated from plants [16,17], marine [18,19], or microbial sources [20,21,22], and found to belong to various types such as saponins [23,24], alkaloids [25], pyrones [26], isochromenes [27], diterpenes[28], flavonoids [29,30], and isoflavonoids [31].
The isoflavonoids are an important polyphenolic subclass of the flavonoids with a skeleton based on a 3-phenylchroman structure [32]. The antiviral power of several isoflavonoid secondary metabolites has been proven in several scientific reports before. Torvanol A is a sulfated isoflavonoid isolated from the fruits of Solanum torvum and exhibited antiviral activity against herpes simplex virus type 1 with an IC50 value of 9.6 μg mL−1 [33]. Genistein; the major isoflavonoid of soybean seeds inhibited HSV-1 (KOS and 29R strains), and HSV-2 (333 strain) replications with IC50 values of 14.02, 7.76 and 14.12, respectively. In addition, three isoflavone glycosides were obtained from some hypocotyls of soybean seeds and could completely inhibit HIV-induced cytopathic effects and virus-specific antigen expression just six days after infection at a concentration of 0.25 mg mL−1 [34]. Daidzein was reported to inhibit the influenza virus at an IC50 of 51.2 µM [35].
Furthermore, homoisoflavonoids showed great antiviral activity against the enteroviruses, Coxsackievirus B1, B3, B4, A9 and echovirus 30 [36]. Interestingly, a group of synthesized substituted homo-isoflavonoids exhibited promising inhibitory effects against human rhinovirus (HRV) 1B and 14 [37]. These findings inspired us to explore the potential of fifty-nine isoflavonoids (1–59) (Figure 1) as a possible treatment for COVID-19 through in silico examination of their potential to bind with ACE-2 and Mpro receptors.

2. Experimental

Drug-likeness properties were calculated using Lipinski’s rule of five, which suggested that the absorption of an orally administered compound is more likely to be better if the molecule satisfies at least three of the following rules: (i) H bond donors (OH, NH, and SH) ≤5; (ii) H bond acceptors (N, O, and S atoms) ≤10; (iii) molecular weight <500; (iv) logP <5. Compounds violating more than one of these rules could not have good oral bioavailability [38]. The pharmacokinetic properties (ADMET) of isoflavonoids and adherence with Lipinski’s rule of five were calculated using Discovery studio 4.0 software(Accelrys software Inc., San Diego, CA, USA) [39].
The title molecules were investigated with the aid of docking studies using Discovery Studio 4.0 software (Accelrys software Inc., San Diego, CA, USA) for their binding capabilities against ACE-2 and Mpro. The crystal structures of the target proteins were acquired from the RCSB Protein Data Bank (PDB ID: 6LZG, resolution: 2.50 Å [40] and 6LU7, resolution: 2.16 Å [41] for ACE-2 and Mpro, respectively). the co-crystallized ligands 2-acetamido-2-deoxy-β-D-glucopyranose (NAG) and N-[(5-methylisoxazol-3-yl)carbonyl]alanyl-l-valyl-N~1~-((1R,2Z)-4-(benzyloxy)-4-oxo-1-{[(3R)-2-oxopyrrolidin-3-yl]methyl}but-2-enyl)-l-leucinamide (N3) were used as reference molecules against hACE-2 and Mpro, respectively.
At first, water molecules were removed from the complex. Using the valence monitor method, the incorrect valence atoms were corrected. The energy minimization was then accomplished through the application of force fields CHARMM and MMFF94 [42,43,44,45]. The binding sites were defined and prepared for docking processes. Structures of the tested isoflavonoids and the co-crystallized ligands were sketched using ChemBioDraw Ultra 14.0 (PerkinElmer, Waltham, MA, USA) [46] and saved as MDL-SD files. Next, the MDL-SD files were opened, 3D structures were protonated, and energy was minimized by implementing force fields CHARMM and MMFF94, then adjusted for docking. CDOCKER protocol was used for docking studies using CHARMM-based molecular dynamics (MD) to dock the co-crystallized ligands into a receptor binding site [47,48]. In the docking studies, a total of 10 conformers were considered for each molecule. Finally, according to the minimum free energy of binding interaction, the most ideal pose was chosen.
The toxicity parameters for the examined compounds were calculated using Discovery studio 4.0 software (Accelrys software Inc., San Diego, CA, USA). Simeprevir was used as a reference drug. At first, the CHARMM force field was applied then the compounds were prepared and minimized according to the preparation of small molecule protocol. Then different parameters were calculated from the toxicity prediction (extensible) protocol.

3. Results and Discussion

3.1. Pharmacokinetic Profiling Study

3.1.1. Lipinski’s Rule of Five

In the present study, an in silico computational study of compounds (1–59) was performed to determine their physicochemical properties according to the directions of Lipinski’s rule of five [38] (Table 1).
It was found that almost all the tested isoflavonoids followed Lipinski’s rule of five and hence display a drug-like molecular (DLM) nature. The Log P, molecular weight, number of H-bond donors and number of H-bond acceptors of all isoflavonoids are within the accepted values (less than 5, 500, 5 and 10, respectively). with exceptions of compounds (28, 29, 53, 54 and 57) that have log p values of 6.04, 6.07, 6.19, 6.19 and 6.21, respectively.

3.1.2. ADMET Studies

Discovery studio 4.0 software was used to predict ADMET descriptors (absorption, distribution, metabolism, excretion and toxicity) for the selected isoflavonoids using remdesivir as a reference drug. The predicted ADMET parameters of the tested compounds were listed in Table 2. The BBB penetration levels of 6, 10 and 27 were expected to be high. On the other hand, the expected BBB penetration levels of all other isoflavonoids were ranging from medium to low. These results indicate that most of the tested compounds would be less likely to penetrate the CNS.
The plasma protein binding model predicts the binding ability of a ligand with plasma proteins which affects its efficiency. The results revealed that compounds 1, 2, 5, 9, 10, 14, 15, 18, 19, 23–31, 37, 41, 42, 44, 45, 49, 52–54, 56, 57 and 59 were expected to bind plasma protein by more than 95%, while 3, 8, 13, 16, 17, 20–22, 33, 39, 40, 48, 50, 51, 55 and 58 showed a binding pattern of more than 90%. Contrastingly, compounds 4, 6, 7, 11, 12, 32, 34, 35, 38, 43, 46 and 47 were expected to bind the plasma protein less than 90%.
Moreover, all the tested isoflavonoids were predicted to have good absorption behavior better than that of remdesivir. Also, the solubility levels of most compounds were expected to be in the good range (Table 2 and Figure 2).

3.2. Molecular Docking

3.2.1. Validation Process

Validation of the docking procedures was achieved via re-docking of the co-crystallized ligands against the active pocket of hACE2 and Mpro. The calculated RMSD values between the re-docked poses and the co-crystallized ones were 2.4 and 2.8 Å. Such values of RMSD indicated the efficiency and validity of the docking processes (Figure 3).

3.2.2. HACE2

Coronavirus spike receptor-binding domain complexed with its receptor hACE-2 (PDB: 6LZG) used as a target for the docking studies of selected isoflavonoids. The results demonstrated that all isoflavonoids bound strongly to hACE-2 with binding energies bitter than that of the co-crystallized ligand (NAG). This indicated that the affinity of the tested isoflavonoids toward hACE-2 is higher than that of the co-crystallized ligand (Table 3). Moreover, almost all the tested isoflavonoids exhibited binding modes similar to that of NAG.
The binding pattern of co-crystallized ligand (NAG) demonstrated single hydrogen bonding interaction with Ser371 residue (Figure 4). NAG showed binding energies of −21.39 kcal mol−1. It was found that most of the tested isoflavonoids exhibited binding modes similar to the reference molecule. Compounds 1 (−30.90 kcal mol–1) and 8 (−27.41 kcal mol−1) demonstrated an additional hydrogen bond with Asn343 residue (Figure 5 and Figure 6). This extra hydrogen bond may account for the relatively high binding affinity of both compounds. Furthermore, compounds 33 (Figure 7) and 56 (Figure 8) were found to have good binding energy values of −36.35 and −34.90 kcal mol−1, respectively. Compound 33 formed a binding mode like that of the reference ligand as it formed one hydrogen bond with Ser371 and seven hydrophobic interactions with Phe374, Phe342, Ser371, Asn343, Cys336, Glu340, and Ser373. Interestingly, compound 56 formed two hydrogen bonds with Ser371 and Cys336 in addition to seven hydrophobic interactions with Phe374, Phe338, Ser371, Val367, Cys336, Leu368, and Ser373.
Such results indicate the significance of the tested isoflavonoids as potential inhibitors for hACE-2. Consequently, such compounds may inhibit the entrance of coronavirus into human cells.

3.2.3. Main Protease (Mpro)

The docking results of isoflavonoids into the active site of coronavirus Mpro (PDB: 6LU7) were listed in Table 4. The results showed that all tested isoflavonoids can bind to Mpro with one or more hydrogen bonds. At the same time, the tested compounds bound to the receptor with free binding energies ranging from −32.19 to −50.79 kcal mol−1, compared to the co-crystallized (binding energy = −62.84 kcal mol−1).
These results revealed that the affinities of the presented isoflavonoids against Mpro are lower than that of N3. Despite that, the binding energies are still considerable, and their binding modes are great which making these isoflavonoids seem to be biologically active ligands to some extent. Figure 9, Figure 10, Figure 11, Figure 12, Figure 13 and Figure 14 illustrate the binding patterns of N3, compound 6 (binding energy = −41.41 kcal mol−1), compound 7 (binding energy = −40.11 kcal mol−1), compound 8 (binding energy = −42.73 kcal mol−1), compound 30 (binding energy = −48.39 kcal mol−1), and compound 53 (binding energy = −46.90 kcal mol−1), respectively.
Compound 30 formed a binding mode like that of the reference ligand as it formed three hydrogen bonds with Glu166, Tyr54, and Asp187. Furthermore, it formed eight hydrophobic interactions with His41, Gln189, His163, Met165, Tyr54, Asp187, Leu167, and Glu166. For compound 53, it formed two hydrogen bonds with Glu166, Phe140. Besides, it formed six hydrophobic interactions with Glu166, Gln189, Leu141, Met165, His172, and Phe140.

3.2.4. Structure-Activity Relationship (SAR)

Based on the binding affinities of the tested compounds against hACE-2, we can obtain valuable SAR. Generally, the tested compounds showed decreased affinity against hACE-2 in descending order of isoflavone derivatives (compounds 34, 33, 35 and 37) > isoflavane derivatives (compounds 50, 53, 57 and 59) > isoflavone derivatives (compounds 19, 20 and 23) > isoflavone derivatives (compounds 1–3) > isoflava-3-ene derivatives (compounds 6–8) > isoflavane derivatives (compounds 4 & 5) > pterocarpanes derivatives (compounds 9–11) (Figure 15).
For isoflavone derivatives (compounds 34, 33, 35 and 37), it was found that compound 34 incorporating 3-hydroxy-3-methylbutyl moiety at 6-position was more active that compound 33 incorporating 3-methylbut-2-en-1-yl moiety at the same position. The latter was more active than compound 35 incorporating 2-hydroxy-3-methylbut-3-en-1-yl moiety at the same position. Compound 37 incorporating 3-methylbut-2-en-1-yl moiety at 8-position was less active than the corresponding members.
With regard to isoflavane derivatives (compounds 50, 53, 57 and 59), it was found that 3-methylbut-2-en-1-yl moiety is critical for binding affinity. compound 50 incorporating this moiety at 3- and 6-positions of 4-chromanone nucleus was more active than compound 53 incorporating this moiety at 5-position of phenyl ring. The latter was more active than compound 57 incorporating 3-methylbut-2-en-1-yl moiety at both 6-position position of 4-chromanone nucleus and 3-position of phenyl ring. Compound 59 incorporating 3-methylbut-2-en-1-yl moiety at both 8-position position of 4-chromanone nucleus and 3-position of phenyl ring was less active than the corresponding members.
Regarding isoflavone derivatives (compounds 19, 20, and 23), it was found that the presence of 1,3-dioxole moiety can affect the affinity depending on it position. compound 19 incorporating 1,3-dioxole moiety at 3,4-positions of phenyl ring was more active than compound 20 incorporating this moiety at 7,8-position of 4H-chromen-4-one nucleus. The latter was more active than compound 23 incorporating 1,3-dioxole moiety at 4,5-position position of phenyl ring.
Then, we investigated the effect of substitutions at isoflavone derivatives on the binding affinity. It was found that the substitutions at 5-position with hydroxyl (compound 1) and methoxy (compound 3) group, increase the binding of isoflavones against hACE-2, with an increased affinity of hydroxyl derivative.
Regarding the effect of substitutions at isoflava-3-ene, it was found that the derivative with additional pyran ring (compound 6) was more active than the corresponding member with free OH group at position-1 of phenyl ring (compound 8) which was more potent than compound 7 incorporating a dioxolan ring.
Observing binding affinities of isoflavane derivatives. It was found that compound 4 incorporating an additional methoxy group at 6 position of phenyl ring showed better binding affinity against hACE-2 than the unsubstituted derivative (compound 5). Such a result may be attributed to the electron donating effect of the methoxy group.
Concerning the activity of different pterocarpan derivatives, it was noted that compound 11, which contained an additional tetrahydrofuran ring attached to the chromene ring, showed better binding affinity inside the hACE-2 than compounds 9 and 10, which contained free OH groups at the chromene ring.

3.3. Toxicity Studies

Toxicity prediction was carried out based on the validated and constructed models in Discovery studio 4.0 software [49,50] as follows. (i) FDA rodent carcinogenicity test which computes the probability of a compound to be a carcinogen. (ii) Carcinogenic potency TD50 which predicts the tumorigenic dose rate 50 (TD50) of a drug in a rodent chronic exposure toxicity test of carcinogenic potency [51]. (iii) Rat maximum tolerated dose (MTD) [52,53]. (iv) Rat oral LD50 which predicts the rat oral acute median lethal dose (LD50) of a chemical [54]. (v) Rat chronic LOAEL which predicts the rat chronic lowest observed adverse effect level (LOAEL) value [55,56]. (vi) Ocular irritancy predicts whether a particular compound is likely to be an ocular irritant and how severe the irritation is in the Draize test [57]. (vii) Skin irritancy predicts whether a particular compound is likely to be a skin irritant and how severe it is in a rabbit skin irritancy test [57].
As shown in Table 5, most compounds showed in silico low toxicity against the tested models. FDA rodent carcinogenicity model indicated that most of the tested compounds are non-carcinogens. Only compounds 6, 9, and 10 were predicted to be carcinogens so that, these compounds do not have the likeness to be used as drugs.
For the carcinogenic potency TD50 rat model, the examined compounds showed TD50 values ranging from 0.44 to 322.42 mg Kg−1 body weight/day which are higher than simeprevir (0.280 mg Kg−1 body weight/day).
Regarding the rat MTD model, the compounds showed MTD with a range of 0.061 to 0.764 g kg−1 body weight higher than simeprevir (0.003 g kg−1 body weight).
Concerning the rat oral LD50 model, the tested compounds showed oral LD50 values ranging from 0.10 to 4.66 mg Kg−1 body weight/day), while simeprevir exhibited an oral LD50 value of 0.21 mg Kg–1 body weight/day. About the rat chronic LOAEL model, the compounds showed LOAEL values ranging from 0.004 to 0.865 g kg−1 body weight. These values are higher than simeprevir (0.002 g kg−1 body weight). Moreover, most of the compounds were predicted to be irritant against the ocular irritancy model. On the other hand, the tested compounds were predicted to be mild or non-irritant against the skin irritancy model.

4. Conclusions

There is an urgent global need to find a cure for COVID-19. The present work is an attempt to find some natural compounds with potential activity against COVID-19. Accordingly, docking studies were carried out for fifty-nine isoflavonoid derivatives against two essential targets (hACE-2 and Mpro). The obtained results showed that the tested isoflavonoids can strongly bind the hACE-2 and Mpro with great binding modes. Based on in silico studies, SARs were established. SAR studies afforded an insight into the pharmacophoric groups which may serve as a guide for the design of new potential anti-COVID-19 agents. Generally, the tested compounds showed decreased affinity against hACE-2 in descending order of isoflavone derivatives (compounds 33–35 and 37) > isoflavane derivatives (compounds 50, 53, 57 and 59) > isoflavone derivatives (compounds 19, 20 and 23) > isoflavone derivatives (compounds 1–3) > isoflava-3-ene derivatives (compounds 6–8) > isoflavane derivatives (compounds 4 and 5) > pterocarpan derivatives (compounds 9–11) Finally, compounds 33 and 56 showed the most acceptable affinity against hACE2; compounds 30 and 53 showed the best docking results against Mpro. In addition, these compounds showed good physicochemical and cytotoxicity profiles. Moreover, in silico investigation of physicochemical properties, ADMET and toxicity studies revealed good properties and general low toxicity. Consequently, this study strongly suggests in vitro and in vivo studies for the most active isoflavonoids against COVID-19.

Author Contributions

M.S.A.: docking studies, A.E.A.: Data curation and Writing the original draft, M.S.T.: Writing original draft, E.B.E.: Resources, I.H.E.: ADMET and toxicity studies, A.M.M.: Writing-review & editing. I.H.E. and A.M.M.: Designed the idea and supervised the work. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding and The APC was funded by AlMaarefa University, Ad Diriyah, Riyadh 13713, Saudi Arabia.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The authors acknowlege Faculty of Pharmacy (Boys), Al-Azhar Universuty, Cairo, Egypt for computer supply.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the compounds are not available from the authors.

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Molecules 26 02806 g001a 550Molecules 26 02806 g001b 550Molecules 26 02806 g001c 550Molecules 26 02806 g001d 550
Figure 1. Structures of the examined isoflavonoids.
Figure 1. Structures of the examined isoflavonoids.
Molecules 26 02806 g001aMolecules 26 02806 g001bMolecules 26 02806 g001cMolecules 26 02806 g001d
Molecules 26 02806 g002 550
Figure 2. The expected ADMET study of the designed compounds and remdesivir.
Figure 2. The expected ADMET study of the designed compounds and remdesivir.
Molecules 26 02806 g002
Molecules 26 02806 g003 550
Figure 3. Superimposition of the co-crystallized poses (green) and the docking pose (maroon) of the same ligands. (Left): hACE2 (RMSD = 2.4 Å), (right): Mpro (RMSD = 2.8 Å).
Figure 3. Superimposition of the co-crystallized poses (green) and the docking pose (maroon) of the same ligands. (Left): hACE2 (RMSD = 2.4 Å), (right): Mpro (RMSD = 2.8 Å).
Molecules 26 02806 g003
Molecules 26 02806 g004 550
Figure 4. The co-crystallized ligand (NAG) docked into ACE-2, forming one H. bond with Ser371.
Figure 4. The co-crystallized ligand (NAG) docked into ACE-2, forming one H. bond with Ser371.
Molecules 26 02806 g004
Molecules 26 02806 g005 550
Figure 5. Compound 1 docked into ACE-2, forming two H. bonds with Ser371 and Asn343.
Figure 5. Compound 1 docked into ACE-2, forming two H. bonds with Ser371 and Asn343.
Molecules 26 02806 g005
Molecules 26 02806 g006 550
Figure 6. Comound 8 docked into ACE-2, forming two H. bonds with Ser371 and Asn343.
Figure 6. Comound 8 docked into ACE-2, forming two H. bonds with Ser371 and Asn343.
Molecules 26 02806 g006
Molecules 26 02806 g007 550
Figure 7. Compound 33 docked into ACE-2, forming one H. bond with Ser371.
Figure 7. Compound 33 docked into ACE-2, forming one H. bond with Ser371.
Molecules 26 02806 g007
Molecules 26 02806 g008 550
Figure 8. Compound 56 docked into ACE-2, forming two H. bonds with Ser371 and Cys336.
Figure 8. Compound 56 docked into ACE-2, forming two H. bonds with Ser371 and Cys336.
Molecules 26 02806 g008
Molecules 26 02806 g009 550
Figure 9. The co-crystallized ligand (N3) docked into Mpro, forming four H. bonds with Gln189, Tyr 54, Asp 142, Asp187.
Figure 9. The co-crystallized ligand (N3) docked into Mpro, forming four H. bonds with Gln189, Tyr 54, Asp 142, Asp187.
Molecules 26 02806 g009
Molecules 26 02806 g010 550
Figure 10. Compound 6 docked into Mpro, forming one H. bond with Glu166.
Figure 10. Compound 6 docked into Mpro, forming one H. bond with Glu166.
Molecules 26 02806 g010
Molecules 26 02806 g011 550
Figure 11. Compound 7 docked into Mpro, forming one H. bond with Glu166.
Figure 11. Compound 7 docked into Mpro, forming one H. bond with Glu166.
Molecules 26 02806 g011
Molecules 26 02806 g012 550
Figure 12. Compound 8 docked into Mpro, forming three H. bonds with Glu166, Cys145 and His163.
Figure 12. Compound 8 docked into Mpro, forming three H. bonds with Glu166, Cys145 and His163.
Molecules 26 02806 g012
Molecules 26 02806 g013 550
Figure 13. Compound 30 docked into Mpro, forming three H. bonds with Glu166, Cys145 and His163.
Figure 13. Compound 30 docked into Mpro, forming three H. bonds with Glu166, Cys145 and His163.
Molecules 26 02806 g013
Molecules 26 02806 g014 550
Figure 14. Compound 53 docked into Mpro, forming two H. bonds with Glu166, Phe140.
Figure 14. Compound 53 docked into Mpro, forming two H. bonds with Glu166, Phe140.
Molecules 26 02806 g014
Molecules 26 02806 g015 550
Figure 15. Schematic diagram showing the different affinities of isoflavonoids against hACE-2.
Figure 15. Schematic diagram showing the different affinities of isoflavonoids against hACE-2.
Molecules 26 02806 g015
Table
Table 1. physicochemical properties of the tested isoflavonoids.
Table 1. physicochemical properties of the tested isoflavonoids.
Comp.Lipinski’s Rule of Five
Log P aMolecular WightHBD bHBA c
12.14270.2335
22.38254.2324
32.36284.2625
43.16332.3426
53.17302.3225
63.81322.3524
73.09328.3116
82.78256.2534
92.68270.2814
103.48322.3514
113.23338.3525
12−1.50450.41110
132.12300.2636
142.57328.3116
152.10330.2837
162.33344.3127
172.55358.3417
182.34314.2826
192.60326.306
202.61296.2705
212.36284.2625
222.34314.2826
232.58356.3207
242.10330.2837
252.36284.2625
262.59298.215
274.84358.3824
286.04420.4925
296.07420.4925
305.03436.4936
315.03436.4936
323.95418.4326
334.78420.4536
343.68438.447
353.73436.4547
362.90354.3546
375.61422.446
383.9368.3836
391.91288.2546
402.14302.2736
412.46316.326
422.44346.3327
432.465316.326
442.24302.2736
452.48332.347
461.99318.27847
471.88302.2736
484.11340.3735
494.09370.3936
504.09370.3936
514.32384.42226
524.32384.4226
536.19422.5125
546.19422.5125
554.32384.4226
565.72424.4846
576.21392.4824
584.52452.4937
595.95438.5136
a Partition coefficient; b Hydrogen bond donors; c Hydrogen bond acceptors.
Table
Table 2. Predicted ADMET descriptors for the tested isoflavonoids and remdesivir.
Table 2. Predicted ADMET descriptors for the tested isoflavonoids and remdesivir.
CompoundBBB Level aAbsorption Level bPPB cSolubility Level d
13023
22023
33013
42003
52023
61002
72002
82013
92023
101022
112002
124204
133013
143023
153023
163013
173013
183023
192022
202012
213013
223013
232022
243023
253023
262023
271022
284122
294121
304122
314122
322002
334112
344102
354102
364013
374222
384002
393013
403013
413023
423023
433003
443023
454023
464003
473003
482012
494022
504012
512012
522022
534221
544221
552012
564222
574121
584112
59 222
Remdesivir4302
a BBB level, blood brain barrier level, 0 = very high, 1 = high, 2 = medium, 3 = low, 4 = very low. b Absorption level, 0 = good, 1 = moderate, 2 = poor, 3 = very poor. c PBB, plasma protein binding, 0 means less than 90%, 1 means more than 90%, 2 means more than 95%. d solubility level, 0 = extremely low, 1 = very low, 2 = low, 3 = good, 4 = optimal.
Table
Table 3. Free binding energies of the selected isoflavonoids and the co-crystallized ligand (NAG) against hACE-2 and amino acid residues involved in H. bonds and hydrophobic interaction.
Table 3. Free binding energies of the selected isoflavonoids and the co-crystallized ligand (NAG) against hACE-2 and amino acid residues involved in H. bonds and hydrophobic interaction.
Comp.Binding Energy (kcal mol−1)No. of H. BondsInvolved Amino Acid ResiduesAmino Acid Residues Involved in Hydrophobic inTeraction
1−30.902Ser371, Asn343Phe374, Gly339, Ser371, Phe338, Phe342
2−27.841Ser371Phe338, Phe342, Gly339
3−28.131Ser371Phe374, Phe342, Phe338, Gly339
4−25.521Ser371Phe374, Phe342, Phe338, Gly339
5−24.121Ser371Phe374, Phe342, Phe338, Leu368, Gly339
6−26.141Ser371Phe342, Phe338, Phe374
7−25.951Ser371Phe342, Phe338, Phe374
8−27.412Ser371, Asn343Phe374, Phe342, Phe338
9−22.321Ser371Phe374, Phe342, Phe338
10−23.6600Phe374, Phe342, Phe338, Ser371, Gly339
11−24.021Ser371Phe374, Phe342, Phe338
12−31.012Asp364Phe338, Ser371, Leu368, Cys336, Phe374, Val367
13−27.8500Asn343, Ser371, Leu368, Cys336, Phe374, Val367
14−25.171Cys336Phe338, Ser371, Ser373, Leu368, Cys336, Phe374, Val367
15−27.521Cys336Phe374, Phe342, Ser371, Leu368, Cys336, Val367
16−27.421Cys336Ser371, Leu368, Cys336, Phe374, Val367, Gly339
17−25.021Trp436Phe374, Leu368, Val367, Phe342
18−23.371Cys336Phe338, Leu368, Cys336, Phe342, Val367, Asn343
19−30.521Gly339Phe374, Phe338, Ser371, Gly339, Cys336, Leu368, Val367
20−29.5000Phe374, Phe338, Ser371, Cys336, Leu368, Val367
21−24.1000Phe338, Ser371, Cys336, Leu368, Val367, Phe374
22−28.661Cys336Asn434, Phe338, Ser371, Cys336, Leu368, Val367
23−33.2000Phe338, Ser371, Cys336, Leu368, Val367, Ser373
24−32.742Ser371, Cys336Phe374, Phe338, Gly339, Cys336, Ser371, Leu368, Phe432
25−24.431Ser373 Gly339, Leu368, Phe338, Ser371, Cys336
26−27.271Ser373Asn343, Gly339, Leu368, Phe338, Ser371, Cys336
27−30.811Cys336Phe374, Phe338, Ser371, Cys336, Leu368, Val367, Phe342, Asn343
28−29.9100Leu368, Val367, Phe342, Asn343, Cys336, Phe338, Ser371,
29−32.762Ser371, Cys336Phe374, Phe338, Ser371, Val367, Cys336, Leu368, Ser373
30−29.122Asn343, Cys336 Phe338, Ser371, Gly339, Cys336, Leu368, Ser373, Asn343
31−30.841Asn364Cys336, Leu368, Ser373, Asn343, Val362, Asn364
32−33.9500Phe338, Val367, Cys336, Leu368, Ser373, Asn440, Asn364
33−36.351Ser371Phe374, Phe342, Ser371, Asn343, Cys336, Glu340, Ser373
34−39.331Asp364Phe338, Phe342, Asn343, Val367, Asp364, Cys336, Leu335, Leu386
35−34.483Cys336, Gly339, Glu340Phe374, Phe338, Val367, Cys336, Leu368, Ser373, Gly339, Glu340
36−34.802Cys336, Gly339Phe338, Leu335, Asn343, Ser373
37−34.372Ser371, Ser373Leu368, Ser371, Asn343, Ser373, Phe338, Phe342
38−30.092Cys336, Gly339Phe338, Leu335, Cys336, Gly339, Asn343, Ser373
39−25.261Ser371Phe374, Phe338, Ser371, Val367, Cys336, Leu368, Ser373
40−23.321Ser373Phe338, Val367, Cys336, Leu368, Ser373
41−29.161Cys336Cys336, Phe338, Val367, Leu368, Ser373
42−32.121Ser371Phe374, Val367, Cys336, Leu368, Ser373, Phe338, Ser371,
43−27.791Ser371Phe374, Phe338, Ser371, Val367, Cys336, Leu368
44−27.531Ser373Phe338, Phe374, Val367, Cys336, Leu368, Ser373
45−31.391Cys336Cys336, Phe342, Val367, Leu368, Gly339, Asp364
46−30.092Cys336, Gly339Phe338, Leu335, Cys336, Gly339, Asn343, Ser373
47−25.1100Phe338, Asn343, Cys336, Leu368, Ser373
48−34.791Cys336Cys336, Asn343, Phe338, Val367, Leu368, Ser373
49−31.791Cys336Phe338, Asn343, Cys336, Leu368, Val367
50–30.391Cys336Cys336, Phe338, Val367, Leu368, Ser373
51−30.811Ser371Phe342, Asn343, Phe374, Ser371, Leu368
52−29.331Gly339Phe338, Leu335, Cys336, Gly339, Val367, Asn343, Ser373
53−33.341Ser373Phe338, Phe374, Val367, Cys336, Leu368, Ser373
54−35.1000Ser371, Ser373, Phe338, Leu335, Cys336
55−29.061Cys336Cys336, Phe342, Val367, Leu335, Ser371, Asn343
56−34.902Ser371, Cys336Phe374, Phe338, Ser371, Val367, Cys336, Leu368, Ser373
57−34.7700 Ser373, Phe338, Phe342, Cys336, Gly339
58−30.221Ser371Phe342, Asn343, Phe374, Ser371, Leu368
59−34.701Ser371Ser373, Asn343, Phe374, Ser371, Leu368, Val367, Leu335
NAG−21.391Ser371.Phe374, Phe342, Phe338
Table
Table 4. Free binding energies of studied isoflavonoids and ligand to coronavirus Mpro and amino acid residues involved in H. bonds and hydrophobic interaction.
Table 4. Free binding energies of studied isoflavonoids and ligand to coronavirus Mpro and amino acid residues involved in H. bonds and hydrophobic interaction.
Comp.Binding Energy (kcal mol−1)No. of H. BondsInvolved
Amino Acid Residues		Amino Acid Residues Involved in Hydrophobic Interaction
1−37.381Glu166Phe140, Leu141, Gln189, His41, Tyr54, Glu166
2−35.911Phe140Phe140, Leu141, Gln189, His41, Tyr54, Glu166
3−36.081Glu166Phe140, Leu141, Gln189, His41, Tyr54, Glu166
4−37.991Glu166Phe140, Leu141, Gln189, His41, Tyr54, Glu166
5−38.452Thr190, Leu141Phe140, Leu141, Gln189, His41, Tyr54, Glu166
6−41.411Glu166Phe140, Leu141, Asn142, His163, Tyr54, Glu166
7−40.111Glu166Phe140, His172, Glu166, His163, His164, Gln189
8−42.733Glu166, Cys145, His163Phe140, Leu141, Glu166, His163, His164, Gln189
9−33.981Phe140.Phe140, Leu141, Gln189, His41, Tyr54, Glu166
10−35.252Glu166, Phe140.Phe140, Leu141, Gln189, His41, Tyr54, Glu166
11−32.191Glu 166Phe140, Leu141, Gln189, His41, Tyr54, Glu166
12−41.553Gln192, His41, Arg188Glu166, Met 165, Gln192, His41, His164, His172
13−40.511Glu 166Met 165, Cys145, His41, Asn142, Glu166
14−39.891Glu 166His163, Met 165, Cys145, His41, Glu189, Glu166
15−37.341Glu166Phe140, Met 165, Asp187, His41, Glu189, Glu166
16−39.056Glu166, Cys145, Thr26Glu166, Cys145, Thr26, His41, Met 165, Glu189, Leu27
17−40.601Gly143Glu166, Cys145, Thr26, His4, Met 165, Gln189, Gln192
18−35.5800Glu166, Phe140, Gly143, Asp187, Met 165, Gln189
19−37.2600Glu166, Phe140, Cys145, Asp142, Met 165, Gln189
20−34.971Glu 166Phe140, Gln189, His41, Ser144, Tyr54, Glu166
21−38.421Phe140Phe140, Leu141, Gln189, His41, Met165, Leu140, Glu166
22−40.141Phe140Phe140, Leu141, Gln189, His164, Met165, Leu140, Glu166
23−40.2400Glu166, Phe140, Leu141, Gln189, His41, Met165, Leu140
24−38.902Phe140, Glu166Glu166, Phe140, Leu141, Gln189, His164, Met165, Leu140, Cys145
25−34.432Phe140, Glu166Glu166, Phe140, His41, Gln189, His164, Met165, Cys145
26−36.391Phe140Glu166, Phe140, His41, Gln189, His164, Met165
27−38.583Gly143, Cys145, Thr26Glu166, Gly143, Gln189, Cys145, Thr26, Met165
28−47.621His41Glu166, Phe140, His41, Gln189, His164, Met165, Cys145, Leu141
29−49.643Glu166, Tyr54, Asp187Phe140, Gln189, His172, Met165, Tyr54, Asp187, Leu167, Glu166
30−48.393Glu166, Tyr54, Asp187His41, Gln189, His163, Met165, Tyr54, Asp187, Leu167, Glu166
31−48.321Glu 166Phe140, Gln189, His41, Met165, Tyr54, Glu166
32−38.311Cys145Gln189, His41, Met165, Cys145, Glu166
33−43.522Gln189, Gly143Met165, Gln189, Gly143, Glu166
34−45.482Glu166, Cys145Glu166, Phe140, His41, Gln189, His164, Met165, Cys145
35−41.381Gly143Glu166, Gly143, Leu107, Gln192, His164, Met165, Cys145
36−42.294His164, Cys145, Ser144, Leu141Gln189, His172, Met165, Glu166 His164, Cys145, Ser144, Leu141
37−48.134Met165, Thr190, His41, Cys145Glu166, Met165, Thr190, His41, Cys145, Gln189
38−43.301Glu 166 Gln189, His163, Met165, Ser144, Glu166, Leu167
39−38.054Glu166, Cys145Glu166, Cys145, Met165, Asn142
40−36.122Glu166, His163Glu166, His163, Phe140, Met165
41−38.223Gln189, Asp187, Tyr54Gln189, Met165, His163, Glu166
42−37.171Glu166Glu166, Leu141, Gln189, Gly143
43−35.411Asp187Glu166, Leu141, Met165, Ser144
44−36.621Glu166Gln189, Met165, His172, Glu166, His163
45−40.484Ser144, Cys145, Thr26, Gly143Cys145, Thr26, His163, Met165, Asn142
46−40.841His163Glu166, His163, Phe140, Met165
47−35.391Glu166Glu166, Asn142, His164, Met165
48−40.401His163Glu166, Leu141, Met165, Gln189
49−43.834Glu166, Cys145, His41Glu166, Cys145, His41, Met165, Asn142, Leu141
50−43.911Glu166Glu166, Leu141, Met165, Gln189
51−46.152Glu166Glu166, Ser144, Gln189, His41
52−41.201Glu166Glu166, Leu141, Met165, Gln189, Asn142
53−46.902Glu166, Phe140Glu166, Gln189, Leu141, Met165, His172, Phe140
54−50.791Glu166Glu166, Gln189, Leu141, Met165, His172
55−40.561Thr26Asn142, Glu166, Asn142, Leu141
56−48.293Glu166, His41Glu166, His41, Met165, Asn142, His164
57−49.892Gly143, Arg188Glu166, Gln189, Leu141, Met165, His163
58−42.632Glu166, Leu141Glu166, Gln189, Leu141, Met165, His172
59−48.112Gly143, Leu141Glu166, Gln189, Met165,
N3(Co-crystallized ligand)−62.844Gln189, Tyr54, Asp142, Asp187.Phe140, Glu166, His172, Thr190, Gln189, Tyr54, Asp142, Asp187.
Table
Table 5. Toxicity properties of isoflavonoids (1–59) and semiprever.
Table 5. Toxicity properties of isoflavonoids (1–59) and semiprever.
Comp.FDA Rodent CarcinogenicityCarcinogenic Potency TD50
(Rat) a		Rat MTD
(Feed) b		Rat Oral LD50 cRat Chronic LOAEL dOcular IrritancySkin Irritancy
1Non-Carcinogen60.470.5161.400.107IrritantNone
2Non-Carcinogen67.140.3341.410.089IrritantNone
3Non-Carcinogen10.430.2250.810.068IrritantNone
4Non-Carcinogen5.690.2310.170.072IrritantNone
5Non-Carcinogen5.730.2340.170.071IrritantNone
6Carcinogen35.330.2390.770.024IrritantNone
7Non-Carcinogen6.230.0960.480.019IrritantNone
8Non-Carcinogen33.450.5291.060.074IrritantMild
9Carcinogen4.430.1220.140.027IrritantMild
10Carcinogen28.520.1260.160.011IrritantNone
11Non-Carcinogen7.510.1920.550.015IrritantNone
12Non-Carcinogen193.960.0780.100.004MildNone
13Non-Carcinogen5.270.2551.070.865MildNone
14Non-Carcinogen9.100.1641.130.325MildNone
15Non-Carcinogen7.320.2882.030.147MildNone
16Non-Carcinogen7.910.2301.670.155MildNone
17Non-Carcinogen8.980.1841.180.152NoneNone
18Non-Carcinogen8.400.2051.690.309MildNone
19Non-Carcinogen0.770.0690.390.130NoneMild
20Non-Carcinogen0.590.0610.200.145NoneMild
21Non-Carcinogen6.400.1811.440.229MildNone
22Non-Carcinogen5.730.2052.360.390MildNone
23Non-Carcinogen0.440.0770.420.282MildMild
24Non-Carcinogen6.880.2884.660.863MildNone
25Non-Carcinogen19.500.1810.970.191NoneNone
26Non-Carcinogen10.750.1451.010.281MildNone
27Non-Carcinogen29.810.1841.740.054MildNone
28Non-Carcinogen19.030.1990.770.035NoneNone
29Non-Carcinogen25.030.0800.350.055SevereNone
30Non-Carcinogen2.330.0970.450.039SevereNone
31Non-Carcinogen2.330.0970.450.039SevereNone
32Non-Carcinogen20.460.1280.260.074MildNone
33Non-Carcinogen73.660.1970.290.013MildMild
34Non-Carcinogen25.440.5260.920.018SevereNone
35Non-Carcinogen6.870.2360.370.013MildNone
36Non-Carcinogen322.420.7640.840.029SevereNone
37Non-Carcinogen165.350.3031.390.008MildNone
38Non-Carcinogen19.210.1530.460.024MildNone
39Non-Carcinogen35.430.5760.700.012SevereNone
40Non-Carcinogen4.9260.2160.440.015MildNone
41Non-Carcinogen6.310.3810.980.075SevereNone
42Non-Carcinogen5.950.4280.710.026MildNone
43Non-Carcinogen6.310.3810.910.044MildNone
44Non-Carcinogen5.810.4751.120.041MildNone
45Non-Carcinogen5.280.4020.760.037MildNone
46Non-Carcinogen3.250.6681.100.174MildNone
47Non-Carcinogen4.020.3950.650.084NoneNone
48Non-Carcinogen126.900.5450.390.009SevereNone
49Non-Carcinogen14.440.2840.320.024MildNone
50Non-Carcinogen14.440.2840.200.008MildNone
51Non-Carcinogen16.340.2260.140.008MildNone
52Non-Carcinogen21.430.2260.460.010MildNone
53Non-Carcinogen18.790.1500.340.008MildNone
54Non-Carcinogen18.790.1500.260.007MildNone
55Non-Carcinogen14.610.2260.320.053SevereNone
56Non-Carcinogen116.750.5620.420.006SevereNone
57Non-Carcinogen177.620.2910.360.004SevereNone
58Non-Carcinogen5.280.1560.180.016MildNone
59Non-Carcinogen15.210.2080.350.014MildNone
SimeprevirNon-Carcinogen0.280.0030.210.002IrritantNone
a TD 50, tumorigenic dose rate 50, Unit: mg kg−1 body weight/day; b MTD, maximum tolerated dose, Unit: g kg−1 body weight; c LD50, median lethal dose, Unit: g kg−1 body weight; d LOAEL, lowest observed adverse effect level, Unit: g kg−1 body weight.
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Alesawy, M.S.; Abdallah, A.E.; Taghour, M.S.; Elkaeed, E.B.; H. Eissa, I.; Metwaly, A.M. In Silico Studies of Some Isoflavonoids as Potential Candidates against COVID-19 Targeting Human ACE2 (hACE2) and Viral Main Protease (Mpro). Molecules 2021, 26, 2806. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092806

AMA Style

Alesawy MS, Abdallah AE, Taghour MS, Elkaeed EB, H. Eissa I, Metwaly AM. In Silico Studies of Some Isoflavonoids as Potential Candidates against COVID-19 Targeting Human ACE2 (hACE2) and Viral Main Protease (Mpro). Molecules. 2021; 26(9):2806. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092806

Chicago/Turabian Style

Alesawy, Mohamed S., Abdallah E. Abdallah, Mohammed S. Taghour, Eslam B. Elkaeed, Ibrahim H. Eissa, and Ahmed M. Metwaly. 2021. "In Silico Studies of Some Isoflavonoids as Potential Candidates against COVID-19 Targeting Human ACE2 (hACE2) and Viral Main Protease (Mpro)" Molecules 26, no. 9: 2806. https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26092806

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