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Reviews in Cardiovascular Medicine  2020, Vol. 21 Issue (3): 365-384     DOI: 10.31083/j.rcm.2020.03.118
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Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection
Ramesh K. Goyal1, *(), Jaseela Majeed1, Rajiv Tonk1, Mahaveer Dhobi1, Bhoomika Patel2, Kalicharan Sharma3, Subbu Apparsundaram1
1Delhi Pharmaceutical Sciences and Research University, New Delhi - 110017, Delhi, India
2Institute of Pharmacy, Nirma University, Ahmedabad - 382481, Gujarat, India
3Mankind Research Center, Gurgaon-122050, Haryana, India
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Abstract:

Angiotensin-converting enzyme 2 (ACE2), the host cell-binding site for SAR-CoV-2, poses two-fold drug development problems. First, the role of ACE2 itself is still a matter of investigation, and no specific drugs are available targeting ACE2. Second, as a consequence of SARS-CoV-2 interaction with ACE2, there is an impairment of the renin-angiotensin system (RAS) involved in the functioning of vital organs like the heart, kidney, brain, and lungs. In developing antiviral drugs for COVID-19, ACE2, RNA-dependent RNA polymerase (RdRp), and the specific enzymes involved in the viral and cellular gene expression have been the primary targets. SARS-CoV-2 being a new virus with unusually high mortality, there has been a need to get medicines in an emergency, and the drug repurposing has been a primary strategy. Considering extensive mortality and morbidity throughout the world, we have made a maiden attempt to discover the drugs interacting with RAS and identify the lead compounds from herbal plants using molecular docking. Both host ACE2 and viral RNA-dependent RNA polymerase (RdRp) and ORF8 appear to be the primary targets for the treatment of COVID-19. While the drug repurposing of currently approved drugs seems to be one strategy for the treatment of COVID-19, purposing phytochemicals may be another essential strategy for discovering lead compounds. Using in silico molecular docking, we have identified a few phytochemicals that may provide insights into designing herbal and synthetic therapeutics to treat COVID-19.

Key words:  COVID-19      ACE2      SARS-CoV-2      antiviral      phytoconstituents      molecular docking     
Submitted:  20 June 2020      Revised:  21 September 2020      Accepted:  23 September 2020      Published:  30 September 2020     
*Corresponding Author(s):  Ramesh K. Goyal     E-mail:  goyalrk@gmail.com

Cite this article: 

Ramesh K. Goyal, Jaseela Majeed, Rajiv Tonk, Mahaveer Dhobi, Bhoomika Patel, Kalicharan Sharma, Subbu Apparsundaram. Current targets and drug candidates for prevention and treatment of SARS-CoV-2 (COVID-19) infection. Reviews in Cardiovascular Medicine, 2020, 21(3): 365-384.

URL: 

https://rcm.imrpress.com/EN/10.31083/j.rcm.2020.03.118     OR     https://rcm.imrpress.com/EN/Y2020/V21/I3/365

Fig. 1.  Overview of SARS-CoV-2 infection and renin-angiotensin system: During the COVID-19 infection, the SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptors present on the cell surface which undergo endocytosis, and the virus enters inside the cell. Upon entering the cell, it synthesizes RNA using the host metabolic processes in which enzyme RNA dependent RNA polymerase (RdRp) is essential. Due to cellular damage caused by the virus, the alveolar macrophages generate various proinflammatory cytokines like interleukin-6 (IL-6), macrophage inflammatory protein 1α (MIP1α), monocyte chemoattractant protein 1 (MCP1), MIP1β, interferon γ-induced protein-10 (IP-10) resulting in alterations in the vascular permeability. There is leakage of cytokines, promoting more inflammation with dysfunctional immune responses and infiltration of inflammatory cells like monocytes, macrophages, and T-cells, ultimately producing cytokine storm. There is an infiltration of neutrophils that undergoes degranulation leading to the generation of neutrophil extracellular traps (NETs). The circulating ACE2 converts angiotensin (Ang) I to angiotensin1-9 and angiotensin II to angiotensin1-7. The ACE converts angiotensin I to angiotensin II and angiotensin1-9 to angiotensin1-7. Angiotensin II binds to angiotensin 1 (AT1) receptors to produce vasoconstriction, proinflammatory, profibrotic, prothrombotic, and arrhythmogenic action. Angiotensin II also acts on AT2 receptors to mediate tissue protection. Angiotensin 1-7 binds to the MAS receptor to produce vasodilatory, antiproliferative, anti-inflammatosry, antifibrotic, and antithrombotic actions.

Fig. 2.  3D docking pose of rutin into the ACE2 receptor catalytic domain (Pdbid: 2ajf) showing binding interaction with key amino acid residues of backbone protein. The backbone amino acid residues highlighted with grey colour. Binding interaction (hydrogen bonding) depicted with red dashed lines.

Fig. 3.  2D Ligplot interaction of rutin against ACE2 receptor catalytic domain (Pdbid-2ajf). The pose was in 2D form and all the interactions were depicted by red solid lines, hydrophobic amino acid residue denoted by green colour, positive charge residue denoted by blue colour, charged negative residue denoted by red colour, polar residue were denoted by sky blue colour.

Table 1.  Docking scores and binding free energies of phytoconstituents interacting with ACE2 and interacting amino acids.
LigandPhytoconstituent ACE2 Docking scorekcal/mol ACE2amino acids interactingwith the ligand Binding free energykcal/mol
Positive control GL-1001 -6.8 Ala348, Trp349, Asp350, Asp382, Arg393 -60.2
Negative control Captopril -3.7 Tyr385, ASN394 -25.5
1 Rutin -11.5 Ala348, Asp350, Arg393Ser44, Ser47, Phe390, Asn394 -78.2
2 Verbascoside -10.2 Ala348, Asp350, Asp382Glu375, His378, Phe390, Asn394, Glu402 -90.4
3 Hesperidin -9.5 Ala348, Asp350Trp69, Tyr385 -70.3
4 Luteolin 7-O-glucoside -9.3 Ala348, Arg393 Glu375, Phe390, Glu402 -65.3
5 Naringin -9.2 Ala348, Arg393 -65.2
6 Epigallocatechin gallate -8.6 Ala348, Asp350, Asp382, Arg393  Phe390 -72.0
7 Apigenin-7-O-glucoside -8.1 Ala348, Arg393 Glu375, Asn394 -59.2
8 Hesperetin -7.3 Ala348, Arg393 Phe390, Asn394 -57.5
9 Quercetin -7.0 Ala348, Arg393   Phe390 -57.5
10 Naringenin -6.4 Ala348 Phe390 -51.1
11 Dioscin -6.4 Asp350 -57.0
12 Kaempferol -6.3 Ala348, Arg393 Phe390, Asn394 -52.6
13 Apigenin -6.2 Ala348 Phe390 -50.6
14 Luteolin -6.0 Ala348, Arg393  Phe390 -65.3
15 Solanine -6.0 Ala348 Glu402 -42.2
16 Solamargine -5.6 Phe390 -47.4
17 Galangin -5.3 Arg393 Phe390, Asn394 -44.8
18 Acalyphin -5.2 Asp350, Arg393 Asn394 -46.5
19 Solasodine -4.8 Phe390 -42
20 Lantadene A -4.5 Ala348, Asp350 -54.8
21 Oleanolic acid -4.4 Ala348 Asn394 -29.1
22 Lantadene C -4.0 Asp350 -52.2
23 Lantadene B -3.6 Tyr369 50.0
24 Ricinine -3.2 Tyr385 -20.7
25 Solasonine -2.6 None -30.1
ACE2 amino acids interacting with GL-1001, a selective ACE2 inhibitor, are given in bold.
Table 2.  Docking scores and binding free energies of phytoconstituents interacting with AT1 or AT2 and interacting amino acids.
Ligand-Phytoconstituent AT1 Docking score kcal/mol Binding free energy against AT1kcal/mol AT1 amino acids interacting with the ligand AT2 Docking score kcal/mol AT2 amino acids interacting with the ligand Binding free energy against AT2kcal/mol
OlmesartanAT1 antagonist -8.9 -84.3 Tyr35, Trp84, Thr88, Arg167 -6.5 Arg182,Lys215, Trp100 -78.3
PD12377AT2 antagonist -4.9 -85.6 Tyr87, Tyr92 -6.7 Trp100, Phe129, Arg182, Lys215, Phe272 -82.9
1 Rutin -12.6 -95.2 Tyr35, Thr88, Arg167 Tyr87, Phe182, Tyr184, Asp263, Gln267 -11.9 Arg182, Lys215, Phe272 Ser208, Asp279 -91.5
2 Verbascoside -12.3 -91.7 Arg167 Tyr184,Trp253, Gln257 Asp263 -11.6 Arg182, Lys215 Tyr108, Thr276, Asp279, Trp283 -94.8
3 Hesperidin -11.6 -90.3 Tyr35 Ser16, Cys18, Ala21, Tyr87 -10.2 Arg182, Lys215 Thr276, Asp279 -91.0
4 Luteolin 7-O-glucoside -10.5 -76.8 Tyr35 Cys180, Tyr292 -9.7 Arg182, Lys215 Thr125 -68.0
5 Naringin -10.7 -84.1 Tyr35, Thr88, Arg167 Pro19, Ala21, Arg23, Tyr87 -10 Lys215 Cys195, Thr276, Asp279 -83.9
6 Epigallocatechin gallate -7.2 -72.8 Arg167 Ala21, Arg23, Tyr87, Tyr92, Asp263 -9.4 Lys215, Phe272  Thr178 -78.2
7 Apigenin-7-O-glucoside -11.1 -74.9 Arg167 Ala21, Tyr87, Asp281 -10.2 Arg182 Tyr51, Thr125 -74.3
8 Hesperetin -8.0 -50.5 Arg167 Tyr87 -7 Lys215, Phe272  Thr178 -57.7
9 Quercetin -8.4 -55.3 Tyr35  Ala21, Tyr87, Tyr92 -7.5 Lys215, Phe272 Thr178 -54.2
10 Naringenin -8.0 -45.5 Arg167  Tyr87 -7.7 Thr125 Arg182 -50
11 Dioscin -10.0 -58.8 Tyr87 -8.2 Thr125 -54.2
12 Kaempferol -7.0 -46.5 Tyr35, Arg167 Tyr87 -7.3 Phe272 Thr125, Ile304 -50.3
13 Apigenin -7.8 -45.3 Arg167 -7.7 Arg182 Thr125 -48.5
14 Luteolin -9.0 -47.4 Arg167 -7.3 Lys215, Phe272  Thr178 -52.8
15 Solanine -8.4 -33.5 None -8.9 Arg182 -50.1
Fig. 4.  3D docking pose of rutin into the AT1 receptor (Pdbid-4zud) showing binding interaction with key amino acid residues of backbone protein. The backbone amino acid residues highlighted with grey colour while rutin highlighted by green colour. Binding interaction (hydrogen bonding) depicted with red dashed lines. Pi-pi stacking interaction was denoted by blue dashed lines.

Fig. 5.  2D Ligplot interaction of rutin docked in to the AT1 receptor catalytic domain (Pdbid-4zud). The pose was in 2D form and all the interactions were depicted by red solid lines, hydrophobic amino acid residue denoted by green colour, positive charge residue denoted by blue colour, charged negative residue denoted by red colour, polar residue were denoted by sky blue colour.

Fig. 6.  3D docking poses of rutin in to the AT2 receptor catalytic domain (Pdbid-4unf) showing binding interaction with key amino acid residues of backbone protein. The backbone amino acid residues highlighted with grey colour while rutin highlighted by brown colour. Binding interaction (hydrogen bonding) depicted with red dashed lines. Pi-pi stacking interaction was denoted by blue dashed lines.

Fig. 7.  2D Ligplot interaction of rutin docked in to the AT2 receptor catalytic domain (Pdbid-4unf). The pose was in 2D form and all the interactions were depicted by red solid lines, hydrophobic amino acid residue denoted by green colour, positive charge residue denoted by blue colour, charged negative residue denoted by red colour, polar residue were denoted by sky blue colour.

Table 3.  Docking scores and binding free energies of phytoconstituents interaction with viral RdRp and ORF8 interacting amino acids.
Ligand Phytoconstituent RdRp Docking score kcal/mol Binding free energy against RdRp kcal/mol RdRp amino acids interacting with the ligand ORF8 Docking score kcal/mol ORF8 amino acids interacting with the ligand Binding free energy against ORF8 kcal/mol
Uridine Triphosphate -6.7 -56.8 Lys551, Arg553, Arg555, Lys621, Asp760 ND   ND ND
Thymidine derivative -6.5 -53.2 Arg553, Cys622 ND ND ND
Remedisvir -6.7 -61.5 Lys551, Arg555 ND ND ND
metabolite Ser549
1 Rutin -9.0 -90.6 Arg555 -10.9 Tyr42, His45, His58, Lys61, His87 -68.9
Ile548, Arg553, Asp623, Asp760
2 Verbascoside -7.4 -132.7 Lys551, Arg555, -9.9 Lys61, Lys90 -72.7
Asp760
Asp618, Cys622
3 Hesperidin -10.0 -98.1 Arg555 -14.5 Phe43, His45, His58, Lys61, His87, Asn97 -97.5
Lys545, Ile548, Asp845
4 Luteolin 7-O-glucoside -8.5 -102 Ile548, Ser759, Arg836 -13.1 His58, His87, Tyr42 -74.4
5 Naringin -9.6 -90.9 Asp760 -11.2 His58, His87, Lys90 -63.2
Ser549, Tyr619, Asp623,
6 Epigallocatechin gallate -5.2 -103.7 Ile548, Ser814 -11.6 Tyr42, His58 -54.2
7 Apigenin-7-O-glucoside -8.6 -90.7 Arg555, Asp760 -12.6 Tyr42, His58, His87 -74.8
Ile548
8 Hesperetin -6.1 -61.5 Arg555 -9.7 His87 -51.5
Ser682
9 Quercetin -7.8 -62.6 Arg555 -10.5 His87 -53.7
Ser682
10 Naringenin -6.4 -43.6 Ser682 -9.3 His58, His87 -46.9
11 Dioscin -5.9 -100  Tyr619 -4.2 Lys90 -40.1
12 Kaempferol -5.7 -53.7 Arg555 -9.8 His87 -50.1
13 Apigenin -5.5 -52.1 Arg555 -9.0 His87 -52.1
Ser682
14 Luteolin -6.4 -54.1 Arg555 -10.0 His87 -52.2
Ser682
15 Solanine -6.1 -102.9 Ser682 -5.5 His87 -51.2
16 Solamargine -10.8 -72.8 Tyr619 -4.7 Trp42 -43.2
17 Galangin -5.6 -52.1 Arg555 -9.8 Tyr42, His58, His87 -51.2
18 Acalyphin -5.6 -46.6 Asp760 -6.6 His87 -37.5
Asp618, Lys621
19 Solasodine -4.2 -58.6 Asn691 -2.0 Leu91 -16.9
20 Oleanolic acid -3.0 -58.2 Ser549, Tyr619 -1.2 Lys90 -69.2
SARS-CoV-2 RdRp amino acids interacting with uridine triphosphate, are given in bold.
Fig. 8.  3D docking pose of hesperidin in to the RdRp receptor catalytic domain (Pdbid-7bv2) showing binding interaction with key amino acid residue of backbone protein. The backbone amino acid residues highlighted with grey colour while hesperidin highlighted by grey colour, Binding interaction (hydrogen bonding) depicted with red dashed lines. Ionic interaction was denoted by green dashed lines.

Fig. 9.  2D Ligplot interaction of hesperidin docked in to the RdRp receptor catalytic domain (Pdbid-7bv2). The pose was in 2D form and all the interactions were depicted by violet solid lines, hydrophobic amino acid residue denoted by green colour, positive charge residue denoted by blue colour, charged negative residue denoted by red colour, polar residue were denoted by sky blue colour.

Fig. 10.  3D docking pose of hesperidin in to the ORF8 receptor catalytic domain (Pdbid-6bb5) showing binding interaction with key amino acid residue of backbone protein. The backbone amino acid residues highlighted with grey colour while hesperidin highlighted by brown colour Binding interaction (hydrogen bonding) depicted with red dashed lines. pi-pi interaction was denoted by blue dashed lines.

Fig. 11.  2D Ligplot interaction of hesperidin docked in to the ORF8 receptor catalytic domain (Pdbid-6bb5). The pose was in 2D form and all the interactions were depicted by violet solid lines, hydrophobic amino acid residue denoted by green colour, positive charge residue denoted by blue colour, charged negative residue denoted by red colour, polar residue were denoted by sky blue colour.

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