Predicted antiviral drugs Darunavir, Indinavir and Rimantadine can potentially bind to neutralize COVID-19 conserved proteins

doi:10.21203/rs.3.rs-22247/v1

Background: Novel Coronavirus disease 2019 or COVID-19 has become a threat to human society due to fast spreading and increasing mortality. It uses vertebrate hosts and presently deploying humans. Life cycle and pathogenicity of COVID-19 have already been deciphered and possible drug target tests are on the way.

Results: The present study was aimed to analyze conserved Endoribonuclease, protease and replicase proteins of the virus as targets to all known drugs. A bioinformatics based web server Drug ReposeER predicted several drug binding motifs in these analyzed proteins. Results revealed that anti-viral Darunavir, Indinavir and Rimantadine were the most potent to have 3D-drug binding motifs on COVID-19 proteins.

Conclusions: Repurposing of the antiviral drugs Darunavir, Indinavir and Rimantadine to treat COVID-19 infected persons could be useful that can potentially prevent thousands of human mortality.

Infectious Diseases

COVID-19

Antiviral drugs

Drug binding 3D-motif

Darunavir

Indinavir

Rimantadine

Endoribonuclease

Main Protease

Replicase

COVID-19 has become a menace to the human kind that imposed epidemic condition. Great efforts are being carried out by the scientists to develop vaccine or a potent drug to curb human mortality. The virus has several types of vertebrate hosts including human and transmission occurs through direct contact or aerosols. It’s a positive sense RNA virus with a genome of ~30 kb (1, 2). Like every animal virus their proteins hijack the cellular machineries to complete life cycle. These proteins are of great interest to the scientists to develop specific drug or vaccine against them. Search and trial for potential inhibitory drugs is on the way but they were proven ineffective to prevent patient death (3). The present work based on the fact that enzymes of any virus remain structurally and chemically conserver as they have to interact with human proteins and have to carry out same biochemical processes within cell. In the present study three structurally known enzymes of COVID-19, i.e., NSP15 endoribonuclease (PDB ID: 6VWW) (4), Main Protease (PDB ID: 6M03) (5), and NSP9 Replicase (PDB ID: 6W4B) (6) have been analyzed using Drug ReposeER web server program (http://27.126.156.175/drreposed/) (7) for their possible binding sites (8) to all drugs available in drug bank. Coronavirus endoribonuclease (NSP15/EndoU) is a hexameric protein that preferentially recognizes and cleaves RNA (1, 2, 9) and EndoU also evades host mediated viral double-stranded RNA recognition (10). Main protease (M^pro) or NSP5 is essential for viral replication (1, 2, 11) whereas NSP9 replicase is dimeric and involved in viral RNA synthesis (1, 2, 12, 13).

DrReposER predicted numerous potential 3D-motifs of both left (L) and right (R) superpositions for 6VWW, 6M03, 6W4B (Supplementary 1, Supplementary 2, Supplementary 3). Known drugs that bind these motifs either bind human cellular, bacterial or viral proteins. From the hit results 16 anti-viral drugs were selected for their target specificities and effectiveness. The anti-viral drugs were presented in tabular formats (Table 1 – 3). Results showed that 21 unique potential 3D-motifs were predicted for (6VWW) Endoribonuclease (Table 1), 13 for (6M03) main Protease (Table 2) and 6 for (6W4B) Replicase (Table 3). The drugs were further analyzed and compared for their binding towards all the target proteins (Table 4). Results revealed that Darunavir (Ligand ID: 017), Indinavir (Ligand ID: MK1) and S-adenosylmethionine (SAM) have binding sites both on 6VWW and 6M03, whereas Ribavirine and Rimantadine (Ligand ID: RIM) have binding sites on 6M03 and 6W4B. Moreover, Tipranavir binding was predicted on all target proteins (Table 4). Other anti-viral drugs, i.e., Amprenavir, Atazanavir, Lopinavir, Saquinavir, Torimifene, Amphetamine, Nelfinavir, Nevirapine, Ritonavir and Grazoprevir had binding sites on any of the three analyzed proteins. From the results Darunavir, Indinavir and Rimantadine have been prioritized for their greater inhibitory binding to these proteins. Darunavir had 5 binding motifs (3LEU-23VAL-6VAL, 72ILE-157GLY-156VAL, 73LEU-80ILE-86ILE, 300LEU-212ILE-253ILE, and 300LEU-296ILE-253ILE) on 6VWW and 2 binding motifs (109GLY-200ILE-293PRO and 133ASN-195GLY-194ALA) on 6M03 (Table1,2,4, Fig 1,2). Indinavir had 3 binding motifs (122VAL-119PRO-80ILE, 173VAL-170GLY-169ILE and 321VAL-344PRO-323ILE) on 6VWW and a single motif (106ILE-109GLY-200ILE) on 6M03 (Table1,2,4 Fig 1,2) whereas Rimantadine had 3 predicted binding sites (255ALA-254SER-251GLY, 255ALA-254SER-258GLY and 285ALA-284SER-283GLY) on 6M03 and 3 binding sites (111VAL-108ALA-106SER, 111VAL-109ALA-106SER and 109ALA-106SER-105GLY) on 6W4B (Table2,3,4, Fig 2,3). Again minimum Root Mean Square Deviation (RMSD) for 6VWW-Darunavir and 6M03-Darunavir binding was 0.77 Å and 0.76 Å and known interaction for binding involves maximum of 22 and 26 residues respectively (Table 1,2). RMSD and residue binding of Indinavir to 6VWW and 6M03 were 0.87 Å & 0.82 Å, and 21 & 22 residues respectively (Table 1,2). Rimantadine accounts for 6M03 and 6W4B binding with RMSD of 0.88 Å & 0.90 Å and 9 & 10 residues respectively (Table 2,3).

From the resulted Table 4, it is evident that SAM, Tipranavir and Ribavirin showed predicted binding sites for the targets, however, Darunavir, Indinavir and Rimantadine binding outnumber them. Again some target sites coincide with Darunavir, Indinavir or Rimantadine as can be seen for Saquinavir. Hence, Darunavir, Indinavir and Rimantadine could be the choice of drugs to treat COVID-19. Along with these SAM may be administered which is not a classical anti-viral drug and have implications to treat Liver problems. Darunavir (DRV- Drugbank ID: DB01264) and Indinavir (IDV- Drugbank ID: DB00224) are members of Protease-inhibitor family of antiviral drugs to ward off HIV, on the other hand Rimantadine (RIM- Drugbank ID: DB00478) is an Influenza virus inhibitor (14). These drugs are potent to inhibit their designated targets and results of this analysis also provide data that these can effectively bind COVID-19 targeted proteins to inhibit disease outcome and prevent human death.

The findings strongly suggest that combination of antiviral drugs, Darunavir, Indinavir and Rimantadine can potentially inhibit COVID-19 enzymatic proteins. The targeted proteins are highly conserved and due to this reason inhibiting those can effectively inhibit the entire virus. Where no such drugs are proving ineffective to save thousands of lives, these predicted combinations of drugs must be clinically tested to cure patients. Practical implication of the findings can effectively save thousands of valuable lives. On the other hand vaccine development is on the way but the limitations of vaccine use is that it can not protect already infected patients showing disease outcomes and in those cases only effective drugs can save lives.

Key Resources Table

Resource	Source	Identifier
Deposited Data
COVI-19 Endonuclease 3D-structure	Kim et al., 2020	PDB ID: 6VWW
COVI-19 Main Protease 3D-structure	Zhang et al., 2020	PDB ID: 6M03
COVI-19 Replicase 3D-structure	Tan et al., 2020	PDB ID: 6W4B
Web Server
DrReposER	Ab Ghani et al., 2019	http://27.126.156.175/drreposed/

DrReposER has been used to find binding interfaces or 3D-motifs of target proteins (PDB ID: 6VWW, 6M03, 6W4B) for all possible drugs. The program uses SPRITE and ASSAM web servers to find amino acid side chains (8, 15, 16, 17). Drug ReposER compares structurally similar side chain arrangements from PDB repository and assign hit results for different drug targets in the query PDB ID.

Ethics approval and consent to participate: Not applicable

Consent for publication : Not applicable

Availability of data and materials : Not applicable

Competing interests : The author has no competing interests

Funding : Not applicable

Authors' contributions : Dr. Umesh Chandra Halder has designed, performed all analysis, written the paper, and prepared the images and Tables.

Acknowledgements : Not applicable

Chen Y, Liu Q, Guo D. Emerging coronaviruses: Genome structure, replication, and pathogenesis. J Med Virol. 2020;92:418-423.
Fehr AR, Perlman S. Coronaviruses: an overview of their replication and pathogenesis. Methods Mol Biol.2015;1282: 1-23.
Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther.2020;14:58-60.
Kim Y, Jedrzejczak R, Maltseva N, Endres M, Godzik A, Michalska K, et al. Crystal Structure of NSP15 Endoribonuclease from SARS CoV-2. PDB data. 2020. https://www.rcsb.org/structure/6VWW.
Zhang B, Zhao Y, Jin Z, Liu X, Yang H, Rao Z. The crystal structure of COVID-19 main protease in apo form. PDB data. 2020. http://www.rcsb.org/structure/6M03.
Tan K, Kim Y, Jedrzejczak R, Maltseva N, Endres M, Michalska K, et al. The crystal structure of Nsp9 RNA binding protein of SARS CoV-2. PDB data. 2020 http://www.rcsb.org/structure/6W4B.
Drug ReposeER web server program. http://27.126.156.175/drreposed/. Accessed 25 March 2020.
Ab Ghani NS, Ramlan EI, Firdaus-Raih M. Drug ReposER: a web server for predicting similar amino acid arrangements to known drug binding interfaces for potential drug repositioning. Nucleic acids research. 2019;47:W350-W356.
Bhardwaj K, Sun J, Holzenburg A, Guarino LA, Kao CC. RNA recognition and cleavage by the SARS coronavirus endoribonuclease. J Mol Biol. 2006;361:243-56.
Deng X, Baker SC. An "Old" protein with a new story: Coronavirus endoribonuclease is important for evading host antiviral defenses. Virology. 2018;517:157-163.
Wang F, Chen C, Tan W, Yang K, Yang H. Structure of Main Protease from Human Coronavirus NL63: Insights for Wide Spectrum Anti-Coronavirus Drug Design. Sci Rep. 2016;6:22677.
Sutton G, Fry E, Carter L, Sainsbury S, Walter T, Nettleship J, et al. The nsp9 replicase protein of SARS-coronavirus, structure and functional insights. Structure. 2004;12:341-53.
Ziebuhr J. The coronavirus replicase. Curr Top Microbiol Immunol. 2005;287:57-94.
De Clercq E, Li G. Approved Antiviral Drugs over the Past 50 Years. Clin Microbiol Rev. 2016;29:695-747.
Nadzirin N, Gardiner E, Willett P, Artymiuk PJ, Firdaus-Raih M. SPRITE and ASSAM: web servers for side chain 3D-motif searching in protein structures. Nucleic Acids Res.2012;40:W380-6.
Spriggs RV, Artymiuk PJ, Willett P. Searching for patterns of amino acids in 3D protein structures. J Chem Inf Comput Sci. 2003;43:412-21.
Artymiuk PJ, Poirrette AR, Grindley HM, Rice DW, Willett P. A graph-theoretic approach to the identification of three-dimensional patterns of amino acid side-chains in protein structures.J Mol Biol. 1994;243:327-44.

Table 1. Possible binding sites of NSP15 against known anti-viral drugs. Features of different drug binding motifs. HIV-1-Human Immunodeficiency virus 1, RMSD- Root Mean Square Deviation, Å-angstrom, ILE-isoleucine, GLY-glycine, VAL-valine, LEU-leucine, PRO-proline, ASP-aspartic acid
					(6VWW) NSP15 ENDORIBONUCLEASE OF COVID-19
DRUGS		TOTAL BINDING SITES
AMPRENAVIR	KNOWN SIMILAR TARGET MOLECULE				PROTEASE, HIV-1
	BINDING PROPERTIES	2	1	SUPERPOSITION TYPE	L
				RMSD	0.90 Å
				AMINO ACID TARGETS OF DRUG	72 ILE 157 GLY 156 VAL
				NO. OF RESIDUES IN KNOWN BINDING	25
				HUMAN SIMILAR TARGETS	4
			2	SUPERPOSITION TYPE	L
				RMSD	0.66 Å
				AMINO ACID TARGETS OF DRUG	251 LEU 276 VAL 296 ILE
				NO. OF RESIDUES IN KNOWN BINDING	19
				HUMAN SIMILAR TARGETS	5

ATAZANAVIR	KNOWN SIMILAR TARGET MOLECULE				PROTEASE, HIV-1
	BINDING PROPERTIES	1	1	SUPERPOSITION TYPE	L
				RMSD	0.83 Å
				AMINO ACID TARGETS OF DRUG	72 ILE 157 GLY 156 VAL
				NO. OF RESIDUES IN KNOWN BINDING	24
				HUMAN SIMILAR TARGETS	4

DARUNAVIR	KNOWN SIMILAR TARGET MOLECULE				PROTEASE, HIV-2
	BINDING PROPERTIES	5	1	SUPERPOSITION TYPE	L
				RMSD	1.00 Å
				AMINO ACID TARGETS OF DRUG	3 LEU 23 VAL 6 VAL
				NO. OF RESIDUES IN KNOWN BINDING	20
				HUMAN SIMILAR TARGETS	6
			2	SUPERPOSITION TYPE	L
				RMSD	0.95 Å
				AMINO ACID TARGETS OF DRUG	72 ILE 157 GLY 156 VAL
				NO. OF RESIDUES IN KNOWN BINDING	20
				HUMAN SIMILAR TARGETS	10
			3	SUPERPOSITION TYPE	R
				RMSD	0.77 Å
				AMINO ACID TARGETS OF DRUG	73 LEU 80 ILE 86 ILE
				NO. OF RESIDUES IN KNOWN BINDING	22
				HUMAN SIMILAR TARGETS	12
			4	SUPERPOSITION TYPE	R
				RMSD	0.91 Å
				AMINO ACID TARGETS OF DRUG	300 LEU 212 ILE 253 ILE
				NO. OF RESIDUES IN KNOWN BINDING	22
				HUMAN SIMILAR TARGETS	12
			5	SUPERPOSITION TYPE	L
				RMSD	0.77 Å
				AMINO ACID TARGETS OF DRUG	300 LEU 296 ILE 253 ILE
				NO. OF RESIDUES IN KNOWN BINDING	22
				HUMAN SIMILAR TARGETS	12

INDINAVIR	KNOWN SIMILAR TARGET MOLECULE				PROTEASE RETROPEPSIN, HIV-1
	BINDING PROPERTIES	3	1	SUPERPOSITION TYPE	R
				RMSD	0.99 Å
				AMINO ACID TARGETS OF DRUG	122 VAL 119 PRO 80 ILE
				NO. OF RESIDUES IN KNOWN BINDING	21
				HUMAN SIMILAR TARGETS	6
			2	SUPERPOSITION TYPE	R
				RMSD	0.87 Å
				AMINO ACID TARGETS OF DRUG	173 VAL 170 GLY 169 ILE
				NO. OF RESIDUES IN KNOWN BINDING	21
				HUMAN SIMILAR TARGETS	3
			3	SUPERPOSITION TYPE	L
				RMSD	0.96 Å
				AMINO ACID TARGETS OF DRUG	321 VAL 344 PRO 323 ILE
				NO. OF RESIDUES IN KNOWN BINDING	21
				HUMAN SIMILAR TARGETS	6

LOPINAVIR	KNOWN SIMILAR TARGET MOLECULE				PROTEASE, HIV-1
	BINDING PROPERTIES	3	1	SUPERPOSITION TYPE	R
				RMSD	0.90 Å
				AMINO ACID TARGETS OF DRUG	122 VAL 119 PRO 80 ILE
				NO. OF RESIDUES IN KNOWN BINDING	23
				HUMAN SIMILAR TARGETS	6
			2	SUPERPOSITION TYPE	R
				RMSD	0.80 Å
				AMINO ACID TARGETS OF DRUG	247 GLY 248 GLY 236 ILE
				NO. OF RESIDUES IN KNOWN BINDING	27
				HUMAN SIMILAR TARGETS	6
			3	SUPERPOSITION TYPE	L
				RMSD	0.89 Å
				AMINO ACID TARGETS OF DRUG	321 VAL 344 PRO 323 ILE
				NO. OF RESIDUES IN KNOWN BINDING	23
				HUMAN SIMILAR TARGETS	6

SAM (S-adenosylmethionine)	KNOWN SIMILAR TARGET MOLECULE				RNA directed RNA polymerase, Human metapneumovirus
	BINDING PROPERTIES	2	1	SUPERPOSITION TYPE	R
				RMSD	0.83 Å
				AMINO ACID TARGETS OF DRUG	162 VAL 79 ASP 88 ASP
				NO. OF RESIDUES IN KNOWN BINDING	15
				HUMAN SIMILAR TARGETS	10
			2	SUPERPOSITION TYPE	R
				RMSD	0.73 Å
				AMINO ACID TARGETS OF DRUG	162 VAL 79 ASP 273 ASP
				NO. OF RESIDUES IN KNOWN BINDING	15
				HUMAN SIMILAR TARGETS	10

SAQUINAVIR	KNOWN SIMILAR TARGET MOLECULE				PROTEASE, HIV-1
	BINDING PROPERTIES	3	1	SUPERPOSITION TYPE	L
				RMSD	0.81 Å
				AMINO ACID TARGETS OF DRUG	72 ILE 157 GLY 156 VAL
				NO. OF RESIDUES IN KNOWN BINDING	31
				HUMAN SIMILAR TARGETS	11
			2	SUPERPOSITION TYPE	R
				RMSD	0.92 Å
				AMINO ACID TARGETS OF DRUG	122 VAL 119 PRO 80 ILE
				NO. OF RESIDUES IN KNOWN BINDING	31
				HUMAN SIMILAR TARGETS	5
			3	SUPERPOSITION TYPE	L
				RMSD	0.68 Å
				AMINO ACID TARGETS OF DRUG	321 VAL 344 PRO 323 ILE
				NO. OF RESIDUES IN KNOWN BINDING	22
				HUMAN SIMILAR TARGETS	9

TIPRANAVIR	KNOWN SIMILAR TARGET MOLECULE				PROTEASE, HIV-1
	BINDING PROPERTIES	1	1	SUPERPOSITION TYPE	L
				RMSD	0.88 Å
				AMINO ACID TARGETS OF DRUG	72 ILE 157 GLY 156 VAL
				NO. OF RESIDUES IN KNOWN BINDING	27
				HUMAN SIMILAR TARGETS	3

TORIMIFENE	KNOWN SIMILAR TARGET MOLECULE				ENV, GLYCOPROTEIN-1, ZAIRE EBOLA VIRUS
	BINDING PROPERTIES	1	1	SUPERPOSITION TYPE	L
				RMSD	0.88 Å
				AMINO ACID TARGETS OF DRUG	72 ILE 157 GLY 156 VAL
				NO. OF RESIDUES IN KNOWN BINDING	27
				HUMAN SIMILAR TARGETS	3

Table 2. Possible binding sites of Protease against known anti-viral drugs. Features of different drug binding motifs. HIV-1-Human Immunodeficiency virus 1, RMSD- Root Mean Square Deviation, Å-angstrom, ILE-isoleucine, GLY-glycine, VAL-valine, LEU-leucine, PRO-proline, ASP-aspartic acid, ASN-asparagine, ALA-alanine, THR-threonine, LYS-lysine, SER-serine.
										(6M03) MAIN PROTEASE OF COVID-19
DRUGS				TOTAL BINDING SITES
AMPHETAMINE		KNOWN SIMILAR TARGET MOLECULE								Polymerase Polyprotein, HIV-1
		BINDING PROPERTIES		1			1	SUPERPOSITION TYPE		L
								RMSD		0.93 Å
								AMINO ACID TARGETS OF DRUG		122 PRO 120 GLY 28 ASN
								NO. OF RESIDUES IN KNOWN BINDING		16
								HUMAN SIMILAR TARGETS		0

DARUNAVIR		KNOWN SIMILAR TARGET MOLECULE								HIV-1 PROTEASE
		BINDING PROPERTIES		2			1	SUPERPOSITION TYPE		L
								RMSD		1.06 Å
								AMINO ACID TARGETS OF DRUG		109 GLY 200 ILE 293 PRO
								NO. OF RESIDUES IN KNOWN BINDING		26
								HUMAN SIMILAR TARGETS		0
							2	SUPERPOSITION TYPE		R
								RMSD		0.76 Å
								AMINO ACID TARGETS OF DRUG		133 ASN 195 GLY 194 ALA
								NO. OF RESIDUES IN KNOWN BINDING		26
								HUMAN SIMILAR TARGETS		2

INDINAVIR		KNOWN SIMILAR TARGET MOLECULE								PROTEASE RETROPEPSIN, HIV-1
		BINDING PROPERTIES		1			1	SUPERPOSITION TYPE		L
								RMSD		0.81 Å
								AMINO ACID TARGETS OF DRUG		106 ILE 109 GLY 200 ILE
								NO. OF RESIDUES IN KNOWN BINDING		22
								HUMAN SIMILAR TARGETS		4

NELFINAVIR		KNOWN SIMILAR TARGET MOLECULE								PROTEASE RETROPEPSIN, HIV-1
		BINDING PROPERTIES		1			1	SUPERPOSITION TYPE		L
								RMSD		1.05 Å
								AMINO ACID TARGETS OF DRUG		153 ASP 292 THR 293 PRO
								NO. OF RESIDUES IN KNOWN BINDING		30
								HUMAN SIMILAR TARGETS		13

NEVIRAPINE		KNOWN SIMILAR TARGET MOLECULE								REVERSE TRANSCRIPTASE, HIV-1
		BINDING PROPERTIES		1			1	SUPERPOSITION TYPE		R
								RMSD		1.10 Å
								AMINO ACID TARGETS OF DRUG		88 LYS 86 VAL 30 LEU
								NO. OF RESIDUES IN KNOWN BINDING		7
								HUMAN SIMILAR TARGETS		13

RIBAVIRIN		KNOWN SIMILAR TARGET MOLECULE								RNA POLYMERASE, NORWALK VIRUS
		BINDING PROPERTIES		1			1	SUPERPOSITION TYPE		L
								RMSD		1.06 Å
								AMINO ACID TARGETS OF DRUG		198 THR 199 THR 238 ASN
								NO. OF RESIDUES IN KNOWN BINDING		9
								HUMAN SIMILAR TARGETS		2

RIMANTADINE		KNOWN SIMILAR TARGET MOLECULE								M2 PROTEIN, INFLUENZA A
		BINDING PROPERTIES		3			1	SUPERPOSITION TYPE		R
								RMSD		0.95 Å
								AMINO ACID TARGETS OF DRUG		255 ALA 254 SER 251 GLY
								NO. OF RESIDUES IN KNOWN BINDING		9
								HUMAN SIMILAR TARGETS		0
							2	SUPERPOSITION TYPE		L
								RMSD		0.88 Å
								AMINO ACID TARGETS OF DRUG		255 ALA 254 SER 258 GLY
								NO. OF RESIDUES IN KNOWN BINDING		9
								HUMAN SIMILAR TARGETS		0
							3	SUPERPOSITION TYPE		L
								RMSD		1.00 Å
								AMINO ACID TARGETS OF DRUG		285 ALA 284 SER 283 GLY
								NO. OF RESIDUES IN KNOWN BINDING		9
								HUMAN SIMILAR TARGETS		0

RITONAVIR		KNOWN SIMILAR TARGET MOLECULE								POLYMERASE POLYPROTEIN, HIV-1
		BINDING PROPERTIES		1			1	SUPERPOSITION TYPE		L
								RMSD		0.82 Å
								AMINO ACID TARGETS OF DRUG		106 ILE 109 GLY 200 ILE
								NO. OF RESIDUES IN KNOWN BINDING		18
								HUMAN SIMILAR TARGETS		4

SAM (S-adenosylmethionine)		KNOWN SIMILAR TARGET MOLECULE								NSP5, MODOC VIRUS
		BINDING PROPERTIES		1			1	SUPERPOSITION TYPE		L
								RMSD		0.87 Å
								AMINO ACID TARGETS OF DRUG		92 ASP 91 VAL 93 THR
								NO. OF RESIDUES IN KNOWN BINDING		14
								HUMAN SIMILAR TARGETS		10

TIPRANAVIR		KNOWN SIMILAR TARGET MOLECULE								PROTEASE, HIV-1
		BINDING PROPERTIES		1			1	SUPERPOSITION TYPE		L
								RMSD		1.17 Å
								AMINO ACID TARGETS OF DRUG		94 ALA 34 ASP 33 ASP
								NO. OF RESIDUES IN KNOWN BINDING		27
								HUMAN SIMILAR TARGETS		3
Table 3. Possible binding sites of NSP9 against known anti-viral drugs. Features of different drug binding motifs. HIV-1-Human Immunodeficiency virus 1, RMSD- Root Mean Square Deviation, Å-angstrom, ILE-isoleucine, GLY-glycine, VAL-valine, ASP-aspartic acid, ASN-asparagine, ALA-alanine, THR-threonine, LYS-lysine, SER-serine.
									(6W4B) NSP9 Replicase of COVID-19
DRUGS			TOTAL BINDING SITES
GRAZOPREVIR	KNOWN SIMILAR TARGET MOLECULE								NS3 PROTEASE, NS4A PROTEIN, Hepacivirus C
	BINDING PROPERTIES		1		1	SUPERPOSITION TYPE			L
						RMSD			0.94 Å
						AMINO ACID TARGETS OF DRUG			66 ILE 59 LYS 62 GLY
						NO. OF RESIDUES IN KNOWN BINDING			16
						HUMAN SIMILAR TARGETS			8

RIBAVIRIN	KNOWN SIMILAR TARGET MOLECULE								RNA POLYMERASE, NORWALK VIRUS
	BINDING PROPERTIES		1		1	SUPERPOSITION TYPE			R
						RMSD			0.80 Å
						AMINO ACID TARGETS OF DRUG			36 THR 35 THR 34 ASN
						NO. OF RESIDUES IN KNOWN BINDING			09
						HUMAN SIMILAR TARGETS			2

RIMANTADINE	KNOWN SIMILAR TARGET MOLECULE								M2, BM2 PROTEIN, INFLUENZA A,B
	BINDING PROPERTIES		3		1	SUPERPOSITION TYPE			L
						RMSD			0.90 Å
						AMINO ACID TARGETS OF DRUG			109 ALA 106 SER 105 GLY
						NO. OF RESIDUES IN KNOWN BINDING			9
						HUMAN SIMILAR TARGETS			0
					2	SUPERPOSITION TYPE			R
						RMSD			1.10 Å
						AMINO ACID TARGETS OF DRUG			111 VAL 108 VAL 106 SER
						NO. OF RESIDUES IN KNOWN BINDING			10
						HUMAN SIMILAR TARGETS			0
					3	SUPERPOSITION TYPE			R
						RMSD			1.26 Å
						AMINO ACID TARGETS OF DRUG			111 VAL 109 ALA 106 SER
						NO. OF RESIDUES IN KNOWN BINDING			10
						HUMAN SIMILAR TARGETS			0

TIPRANAVIR	KNOWN SIMILAR TARGET MOLECULE								PROTEASE, HIV-1
	BINDING PROPERTIES		1		1	SUPERPOSITION TYPE			L
						RMSD			1.21 Å
						AMINO ACID TARGETS OF DRUG			16 ALA 26 ASP 27 ASP
						NO. OF RESIDUES IN KNOWN BINDING			27
						HUMAN SIMILAR TARGETS			3

Table 4. Comparison of binding sites of all selected drugs. Out of 16 anti-viral drugs 3 have been selected for their greater binding.
DRUGS	6VWW	6M03	6W4B
Amphetamine	-	+	-
Amprenavir	++	-	-
Atazanavir	+	-	-
Darunavir	+++++	++	-
Grazoprevir	-	-	+
Indinavir	+++	+	-
Lopinavir	+++	-	-
Nelfinavir	-	+	-
Nevirapine	-	+	-
Ribavirin	-	+	+
Rimantadine	-	+++	+++
Ritonavir	-	+	-
S-adenosylmethionine	++	+	-
Saquinavir	+++	-	-
Tipranavir	+	+	+
Torimifene	+	-	-

Predicted antiviral drugs Darunavir, Indinavir and Rimantadine can potentially bind to neutralize COVID-19 conserved proteins

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