Predicted antiviral drugs Darunavir, Amprenavir, Rimantadine and Saquinavir can potentially bind to neutralize SARS-CoV-2 conserved proteins
Journal of Biological Research-Thessaloniki volume 28, Article number: 18 (2021)
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 deploys humans. Life cycle and pathogenicity of SARS-CoV-2 have already been deciphered and possible drug target trials are on the way.
The present study was aimed to analyze Non-Structural Proteins that include conserved enzymes of SARS-CoV-2 like papain-like protease, main protease, Replicase, RNA-dependent RNA polymerase, methyltransferase, helicase, exoribonuclease and endoribonucleaseas targets to all known drugs. A bioinformatic based web server Drug ReposeER predicted several drug binding motifs in these analyzed proteins. Results revealed that anti-viral drugs Darunavir,Amprenavir, Rimantadine and Saquinavir were the most potent to have 3D-drug binding motifs that were closely associated with the active sites of the SARS-CoV-2 enzymes .
Repurposing of the antiviral drugs Darunavir, Amprenavir, Rimantadine and Saquinavir to treat COVID-19 patients could be useful that can potentially prevent human mortality.
SARS-CoV-2 has become a menace to the humanity and it imposed unprecedented epidemic condition. Great efforts were carried out by the scientists to develop potent vaccines like Astrazeneca/Oxford , Johnson & Johnson , Moderna , Pfizer/BionTech , Sinopharm, Sinovac , and COVISHIELD , having the potential to curb human mortality. The virus (a positive sense RNA virus with a genome of ~ 30 kb) has several types of vertebrate hosts including humans and transmission occurs through direct contact or aerosols [7, 8]. Like all animal viruses, their proteins hijack the cellular machineries to complete life cycle. These proteins are of great interest to the scientists to develop specific drug(s) or vaccine schemes against them. Search and trial of potential inhibitory drugs such as Remdesivir, Lopinavir-Ritonaviris were on the way but they were proven ineffective to prevent patient death [9,10,11]. The present work is based on the fact that most of the viral non-structural proteins (NSPs) which include enzymes remain structurally and chemically conserved as they have to interact with human proteins to carry out same biochemical processes within cell. SARS-CoV-2 genome encodes 16 non-structural proteins (NSPs), involved in genome replication and transcription [12, 13]. Nsp1 is a transcriptional, translational inhibitor and evades host immune system [14,15,16]. Nsp2 is involved in viral replication, disrupts host cell environment and, along with Nsp3, form proteases [12, 13]. Nsp4 interacts with Nsp3 to mediate viral replication [12, 13]. Main protease(Mpro) or NSP5 is essential for viral replication [7, 8, 12, 13]. Nsp6 generate autophagosomes that assemble replicase proteins [12, 13]. Nsp7, Nsp8 and Nsp12 form RNA polymerase complex [17, 18]. NSP9 replicase is dimeric and involved in viral RNA synthesis [7, 8, 12, 13, 19]. Nsp10 stimulate Nsp14 and Nsp16 which are methyl transferases [14, 20]. The function of Nsp11 is yet to be deciphered [12, 13]. Nsp13 together with Nsp12 exert helicase activity and is involved in capping of viral RNA . Nsp14 has exoribonuclease and N7-methyltransferase activity . Coronavirus endoribonuclease (NSP15/EndoU) is a hexameric protein that preferentially recognizes and cleaves RNA [7, 8, 12, 13, 23] and EndoU also evades host mediated viral double-stranded RNA recognition. Nsp16 has methyltransferase activity and complexes with Nsp10 [7, 8, 12, 13, 24].
In the present study, 11 PDB entries (7K3N, 6WEY, 6M03, 7JLT, 6W4B, 6ZCT, 6M71, 7NIO, 5C8S, 6VWW and 7BQ7) [25,26,27,28,29,30,31,32,33,34,35] representing twelve non-structural proteins and their complexes of SARS-CoV-2, i.e., NSP1, NSP3,NSP5, NSP7-8 complex, NSP9, NSP10, NSP7-8–12 complex, NSP13, NSP14, NSP15 and NSP16-10 complex respectively have been analyzed using Drug ReposeER web server program (http://188.8.131.52/drreposed/)  for their possible binding sites  to all drugs available in drug bank. Only the NSPs having 3D structures available in PDB, have been considered in the study as tertiary structures have utmost requirement to find 3D drug binding interfaces. The drug binding interfaces showed congruence with the known drug binding motifs (Additional file 1: S1, Additional file 2: S2, Additional file 3: S4, Additional file 4: S4, Additional file 5: S5, Additional file 6: S6, Additional file 7: S7, Additional file 8: S8, Additional file 9: S9, Additional file 10: S10 and Additional file 11: S11) .
Results and discussion
DrReposER predicted numerous potential 3D-drug binding motifs of both left (L) and right (R) superpositions for 7K3N, 6WEY, 6M03, 7JLT, 6W4B, 6ZCT, 6M71, 7NIO, 5C8S, 6VWW and 7BQ7 (Additional file 1: S1, Additional file 2: S2, Additional file 3: S4, Additional file 4: S4, Additional file 5: S5, Additional file 6: S6, Additional file 7: S7, Additional file 8: S8, Additional file 9: S9, Additional file 10: S10 and Additional file 11: S11). Known drugs that bind these motifs bind either human, bacterial or viral proteins. Results after analyzing the 3D structures of the target molecules and complexes were further filtered for anti-viral drugs. From the hit results, 14 anti-viral drugs i.e., Amphetamine (Drug bank ID-DB00182), Amprenavir (Drug bank ID-DB00701), Atazanavir (Drug bank ID-DB01072), Darunavir (Drug bank ID-DB01264), Grazoprevir (Drug bank ID-DB11575), Indinavir (Drug bank ID-DB00224), Lopinavir (Drug bank ID-DB01601), Nelfinavir (Drug bank ID-DB00220), Nevirapine (Drug bank ID-DB00238), Ribavirin (Drug bank ID-DB00811), Rimantadine (Drug bank ID-DB00478), Ritonavir (Drug bank ID-DB00503), Saquinavir (Drug bank ID-DB01232), and Tipranavir (Drug bank ID-DB00932) were selected for having unique 3D-drug binding motifs (Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). The findings showed that several anti-viral drugs had binding interfaces on a single protein or protein complexes and moreover, each anti-viral drug had one to several binding motifs (Tables 12 and 13).
Amphetamine (DB00182) targeted only a single binding interface on Nsp5 (6M03) (Tables 3, 12, 13). Amprenavir (DB00701) targeted four binding motifs on Nsp3 (6WEY), three motifs onNsp1 (7K3N), Nsp7-8-12 complex (6M71), Nsp13 (7NIO) and Nsp14 (5C8S), and two binding motifs on Nsp7-8 complex (7JLT), Nsp15 (6VWW) and Nsp16-10 complex (7BQ7) (Tables 2, 1, 7, 8, 9, 4, 10, 11, 12, Figs. 1, 23, 4, 5, 6, 7, 8, 9, 10 and 11). Atazanavir (DB01072) targeted three motifs on Nsp16-10 complex (7BQ7), two motifs on Nsp10 (6ZCT) and single motif each on Nsp1, Nsp7-8-12, Nsp13, Nsp14 and Nsp15 (Tables 11, 6, 12). Darunavir (DB01264) is the most promising drug as it targeted the greatest number of binding motifs and targeted every molecule except Nsp9. It targeted ten motifs on Nsp1 (7K3N), seven motifs on Nsp14 (5C8S), six motifs on Nsp3 (6WEY), five motifs on Nsp15 (6VWW) and Nsp16-10 complex (7BQ7), four motifs on Nsp7-8-12 complex (6M71), three motifs on Nsp10 (6ZCT), two motifs each on Nsp5 (6M03) and Nsp13 (7NIO), respectively and a single motif on Nsp7-8 complex (Tables 1, 9, 2, 10, 11, 7, 6, 3, 8, 4, 12, Figs. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). Grazoprevir (DB11575) targeted two motifs, on Nsp10 (6ZCT) and two on Nsp16-10 complex (7BQ7) and single motif each on Nsp9 and Nsp14 (Tables 6, 11, 5, 9, 12). Indinavir (DB00224) significantly targeted three motifs, each on Nsp13 (7NIO) and Nsp15 (6VWW) (Tables 8, 10, 12). Lopinavir significantly targeted three motifs on Nsp15 and 2 motifs each on Nsp13 and Nsp14 (Tables 10, 8, 9). Nelfinavir targeted two interfaces on Nsp1 and Nsp7-8–12 complexes (Tables 1, 7). On the other hand, Nevirapine targeted only a single motif on Nsp5 (Table 3). Rimantadine (DB00478) significantly targeted five binding interfaces on Nsp14 (5C8S), three binding motifs each on Nsp5 (6M03) and Nsp9 (6W4B), and two motifs on Nsp3 (6WEY), Nsp13 (7NIO), Nsp16-10 (7BQ7) and a single motif on Nsp1, Nsp7-8 and Nsp7-8-12 complex (Tables 9, 3, 5, 2, 8, 11, 1, 4, 7, 12, Figs. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). Ritonavir targeted two motifs on Nsp16-10 complex (Table 11). Saquinavir (DB01232) targeted four motifs on Nsp16-10 complex (7BQ7), three interfaces each on Nsp7-8–12 (6M71) and Nsp15 (6VWW), two motifs on Nsp1 and Nsp14 (5C8S) and a single motif on Nsp3, Nsp7-8, Nsp10 and Nsp13 (Tables 11, 7, 10, 1, 9, 3, 4, 6, 8, Figs. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). Finally, Tipranavir (DB00932) targeted two binding motifs; each on Nsp3, Nsp7-8–12 complex and Nsp14 (Tables 3, 7, 9), whereas single binding interface each on Nsp1, Nsp5, Nsp9, Nsp13, Nsp15 and Nsp16-10 (Table 12).
All the binding results were further compiled and analyzed. Results revealed that Darunavir (DB01264) had 45 unique binding sites and targeted 10 SARS-CoV-2 PDB entries or 10 NSPs (Tables 12, 13). The Lowest Root Mean Square Deviation (RMSD) value of Darunavir among all the target molecules was 0.54 Å for Nsp16-10 complex and maximum number of residues involved in interaction was 27 (Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). Significant binding interfaces were again targeted by Amprenavir (DB00701) and Saquinavir (DB01232) with 22 and 18 (Tables 12, 13), respectively. The two drugs had eight and nine binding partners, respectively (Tables 12, 13). The lowest RMSDs for them were 0.54 Å and 0.52 Å and maximum residues involved in drug-target binding were 28 and 31, respectively (Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). Additionally, Rimantadine (DB00478) had 20 drug binding motifs that targeted nine binding partners (Tables 12, 13) with the lowest RMSD value of 0.67 Å and maximum number of residues involved in binding were 10 (Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). Again, Tipranavir (DB00932) and Indinavir (DB00224) both showed 12 binding motifs for nine and eight binding partners, respectively (Tables 12, 13). Lowest RMSD values for these two drugs were 0.53 Å and 0.72 Å and maximum number of residues involved in binding were 27 and 24, respectively (Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11).
Results showed that Darunavir, Amprenavir, Rimantadine, Saquinavir, Tipranavir and Indinavir were more effective in targeting the twelve SARS-CoV-2 proteins and their complexes (Tables 12, 13). Darunavir is a nonpeptidic benzenesulfonamide inhibitor that targets active site of HIV-1 protease [38, 39]. Amprenavir is a hydroxyethylamine sulfonamide derivative that inhibits HIV-1 protease [40, 41]. Rimantadine is an alkylamine that specifically targets Influenza A virus M2 protein [42,43,44]. Saquinavir is a L-asparagine derivative that acts as HIV-1 protease inhibitor [45, 46]. Tipranavir is a sulfonamide that acts as HIV-1 protease inhibitor . Moreover, Indinavir is a piperazinecarboxamide having HIV-1 protease inhibitory activity [48, 49]. The drug binding interfaces determined in the present study is very much significant as the analysis considered previously known potent binding information between specific drugs and target proteins that were again supported by very low RMSD values of the motifs such as 0.54 Å for both Darunavir and Amprenavir, 0.52 Å for Saquinavir and 0.67 Å for Rimantadine (Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). RMSD values well below 1.0 was indicative of presence of similar drug binding structures or motifs as in active site of HIV-1 protease or M2 of Influenza A and these results emphasized that the selected drugs would effectively target those similar interfaces found on different NSPs of SARS-Cov2 to inhibit them. Furthermore, considering the produced results, it has been proposed that combination of Darunavir, Amprenavir and Rimantadine could effectively target and inhibit all the NSPs that were studied. Darunavir targeted all NSPs except Nsp9, whereas Amprenavir targeted all except Nsp5, Nsp9 and Nsp10 and interestingly Rimantadine complementarily and significantly targeted Nsp5 and Nsp9, which are two key enzymes (Tables 12, 13). However, it has been reported that Darunavir was unable to protect HIV patients from SARS-Cov2 infection who were under Darunavir treatment . Though, the claim has to be experimentally proven. In such cases, if Darunavir fails to prevent infection, then another potent inhibitor Saquinavir, having similar target profiles, could be used in combination along with Amprenavir and Rimantadine, in replacement of Darunavir (Tables 12, 13, 14).
Among the twelve proteins studied, eight were key enzymes involved in viral replication, transcription and life cycle processes. Hence, the study was further extended to provide insight whether the binding motifs of the selected drugs were significant in inhibiting these enzymes possibly by intercepting active sites of those enzymes. Active sites of enzymes are surface regions that are highly conserved and involved in catalysis or substrate binding. In this study, active sites of SARS-CoV-2 enzymes were predicted by a web server, GASS-WEB (http://gass.unifei.edu.br/) that uses Genetic Active Site Search based on genetic algorithms . Active site residues and the drug binding interfaces of the four drugs viz. Amprenavir (478), Darunavir (017), Rimantadine (RIM) and Saquinavir (ROC) were presented in surface topography presentations of each of the enzymes and were analyzed for their inhibitory association. Results revealed that active site residues of the papain- like protease NSP3 were in close association with drug binding motifs of Amprenavir (270D, 252G, 253 V, 335I, 300 V, 304 V, 287L), Darunavir (252G, 227I, 253 V, 335I, 286 V, 297L, 287L), Rimantadine (337G, 333A, 315S, 281 V) and Saquinavir (252G, 253 V, 335I) (Fig. 12, Table 14). Active sites of protease NSP5 were closely apposed to Darunavir (133 N, 194A, 195G, 200I, 109G, 293P) and Rimantadine (254S, 255A, 251G) binding residues (Fig. 13, Table 14). NSP9 active sites were exclusively targeted by Rimantadine (108 V, 109A, 111 V, 106S, 105G) (Fig. 14, Table 14). RNA polymerase NSP12 active sites were targeted by Amprenavir (166 V, 760D, 203G, 204 V, 201I), Darunavir (53 V, 106I, 119I, 203G, 204 V, 201I), Rimantadine (774G, 771A, 772S) and Saquinavir (623D, 817 T, 820 V, 203G, 204 V, 201I) (Fig. 15, Table 14). The helicase NSP13 active residues were targeted by Amprenavir (195I, 151I, 226 V, 258I), Darunavir (195I, 226 V, 258I), Rimantadine (1A, 3G, 523S, 527G) and Saquinavir (258I) (Fig. 16, Table 14). Exoribonuclease NSP14 active sites were closely apposed to Amprenavir (31I, 14I, 87I, 412P), Darunavir (389 V, 26A, 78R, 390D, 108 V, 152L, 118 V, 120 V), Rimantadine (32A, 34G, 35G, 33S) and Saquinavir (31I, 14I, 84R) binding residues (Fig. 17, Table 14). On the other hand, endonuclease NSP15 active sites were targeted by Amprenavir (276 V, 156 V), Darunavir (80I, 23 V, 212I, 156 V, 3L, 86I), and Saquinavir (119P, 80I, 156 V) (Fig. 18, Table 14). Finally, methyltransferase NSP16 active site residues were targeted by Amprenavir (71A, 70G), Darunavir (21 V, 22D, 26A, 71A, 290I, 121A, 200S), Rimantadine (32A, 33S, 34G, 199A, 197 V, 200S) and Saquinavir (71A, 70G) (Fig. 19, Table 14). Close association of drug binding motifs with the active sites indicated that these would interfere with catalytic activity and substrate binding of the enzymes.
Previously, several drug repurposing analysis were performed by several groups to find potential drug inhibitors like sirolimus, dactinomycin, mercaptopurine, melatonin, toremifene, emodin, zotatifin, ternatin-4, hydroxychloroquine, clemastine, Atazanavir, remdesivir, efavirenz, Ritonavir, dolutegravir, carfilzomib, cyclosporine A, azithromycin, favipiravir, Ribavirin, galidesivir and many others against SARS-CoV-2 proteins but their efficacy is questionable in treating and curing COVID-19 patients [52,53,54,55,56,57].
The findings strongly suggested that among the fourteen anti-viral drugs predicted and analyzed, six drugs significantly targeted twelve SARS-Cov2 non structural proteins and specifically the key enzymes. Considering the binding parameters it can be concluded that combination of Darunavir (DB01264), Amprenavir(DB00701) and Rimantadine(DB00478) or Saquinavir (DB01232), Amprenavir (DB00701) and Rimantadine (DB00478) or all the four drugs together can potentially bind and inhibit the cellular activities of these proteins that are essential for viral replication and life cycle. Using anti-viral drug has great advantage in that these have specific target and less or no similar binding partners like Rimantadine had no other binding partners other than SARS-Cov-2 NSPs (Tables 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11). Finally, these predicted drug combinations must be clinically tested to save thousands of lives in the vicinity of limited effectiveness of developed vaccines [58, 59].
Key resources table
SARS-CoV-2 NSP1 3D-structure
PDB ID: 7K3N
SARS-CoV-2 NSP3 3D-structure
PDB ID: 6WEY
SARS-CoV-2 NSP5 3D-structure
PDB ID: 6M03
SARS-CoV-2 NSP7-8 complex 3D-structure
PDB ID: 7JLT
SARS-CoV-2 NSP9 3D-structure
PDB ID: 6W4B
SARS-CoV-2 NSP10 3D-structure
PDB ID: 6ZCT
SARS-CoV-2 NSP7-8-12 complex 3D-structure
PDB ID: 6M71
SARS-CoV-2 NSP13 3D-structure
PDB ID: 7NIO
SARS-CoV-2 NSP14 3D-structure
PDB ID: 5C8S
SARS-CoV-2 NSP15 3D-structure
PDB ID: 6VWW
SARS-CoV-2 NSP16-10 complex 3D-structure
PDB ID: 7BQ7
DrReposERhas been used to find binding interfaces or 3D-motifs of target proteins (PDB ID: 7K3N, 6WEY, 6M03, 7JLT, 6W4B, 6ZCT, 6M71, 7NIO, 5C8S, 6VWW and 7BQ7) for all possible drugs. The program uses SPRITE and ASSAM web servers to find amino acid side chains. Drug ReposER compares structurally similar side chain arrangements from PDB repository and assign hit results for different drug targets in the query PDB ID .
GASS-WEB has been used to predict active sites of SARS-CoV-2 enzymes (NSP3, NSP5, NSP9, NSP12, NSP13, NSP14, NSP15 and NSP16) considered in this study. It uses genetic algorithms to find active sites of enzymes that are meant for catalytic activity or substrate binding .
Availability of data and materials
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List of drug binding hits for 7K3N –NSP1.
List of drug binding hits for 6WEY-NSP3.
List of drug binding hits for 6M03 –NSP5.
List of drug binding hits for 7JLT-NSP7-8.
List of drug binding hits for 6W4B-NSP9.
List of drug binding hits for 6ZCT-NSP10.
List of drug binding hits for 6M71-NSP7-8-12.
List of drug binding hits for 7NIO-NSP13.
List of drug binding hits for 5C8S-NSP14.
List of drug binding hits for 6VWW-NSP15.
List of drug binding hits for 7BQ7-NSP16-10.
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Halder, U.C. Predicted antiviral drugs Darunavir, Amprenavir, Rimantadine and Saquinavir can potentially bind to neutralize SARS-CoV-2 conserved proteins. J of Biol Res-Thessaloniki 28, 18 (2021). https://doi.org/10.1186/s40709-021-00149-2
- Antiviral drugs
- Non-structural proteins