PMC:7291971 / 28114-32284 JSON TXT

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LitCovid-PMC-OGER-BB

LitCovid-PD-FMA-UBERON

{"project":"LitCovid-PD-FMA-UBERON","denotations":[{"id":"T84","span":{"begin":320,"end":323},"obj":"Body_part"},{"id":"T85","span":{"begin":328,"end":335},"obj":"Body_part"},{"id":"T86","span":{"begin":374,"end":378},"obj":"Body_part"},{"id":"T87","span":{"begin":565,"end":568},"obj":"Body_part"},{"id":"T88","span":{"begin":576,"end":579},"obj":"Body_part"},{"id":"T89","span":{"begin":1184,"end":1195},"obj":"Body_part"},{"id":"T90","span":{"begin":1219,"end":1226},"obj":"Body_part"},{"id":"T91","span":{"begin":1899,"end":1906},"obj":"Body_part"},{"id":"T92","span":{"begin":3034,"end":3037},"obj":"Body_part"},{"id":"T93","span":{"begin":3302,"end":3313},"obj":"Body_part"},{"id":"T94","span":{"begin":3972,"end":3979},"obj":"Body_part"}],"attributes":[{"id":"A84","pred":"fma_id","subj":"T84","obj":"http://purl.org/sig/ont/fma/fma67095"},{"id":"A85","pred":"fma_id","subj":"T85","obj":"http://purl.org/sig/ont/fma/fma82775"},{"id":"A86","pred":"fma_id","subj":"T86","obj":"http://purl.org/sig/ont/fma/fma67122"},{"id":"A87","pred":"fma_id","subj":"T87","obj":"http://purl.org/sig/ont/fma/fma67095"},{"id":"A88","pred":"fma_id","subj":"T88","obj":"http://purl.org/sig/ont/fma/fma67095"},{"id":"A89","pred":"fma_id","subj":"T89","obj":"http://purl.org/sig/ont/fma/fma82739"},{"id":"A90","pred":"fma_id","subj":"T90","obj":"http://purl.org/sig/ont/fma/fma82775"},{"id":"A91","pred":"fma_id","subj":"T91","obj":"http://purl.org/sig/ont/fma/fma82775"},{"id":"A92","pred":"fma_id","subj":"T92","obj":"http://purl.org/sig/ont/fma/fma67095"},{"id":"A93","pred":"fma_id","subj":"T93","obj":"http://purl.org/sig/ont/fma/fma82739"},{"id":"A94","pred":"fma_id","subj":"T94","obj":"http://purl.org/sig/ont/fma/fma67257"}],"text":"To address the molecular bases of N7-MTase nsp14 inhibition by the dinucleosides, we performed computational docking studies of the best inhibitor 13 using Autodock Vina. The docking was based on the SARS-CoV nsp14-nsp10 complex structure solved in presence of SAM [35]. SARS-CoV nsp14 is a bifunctional enzyme carrying RNA cap guanine N7-MTase at the C-terminal domain for mRNA capping (which is not influenced by nsp10) and 3′-5′-exoribonuclease at the N-terminal domain for proofreading. The N7-MTase domain exhibits an original fold and the methyl receptor cap RNA (GpppA-RNA) and SAM bind in proximity in a highly constricted pocket to achieve methyltransfer. The compound 13 was modeled in the SAM binding pocket of the SARS-CoV nsp14 structure (PDB ID: 5C8T [35] \u0026 PDB ID: 5NFY [36]). At first sight, the overlay of the N-adenosine of 13 with the adenosine of SAM bounded structure is suitable (Supporting Information, Fig. S4). More interestingly, the nitrobenzenesulfonamide core of 13 binds into a SARS-CoV nsp14 well known binding site formed by Trp385, Phe401, Tyr420, Phe426 and Phe506 (Fig. 3 , Supporting Information, Fig. S5) [35]. Naturally, the side chains of these amino acids enclose the nucleobase guanine of the cap structure. In this cap-binding site, Phe426 was shown to have the largest influence on the N7-MTase activity, and F426A mutation reduced MTase activity by 50%. With 13, the orientation of the Phe426 residue all around the nitrobenzenesulfonamide leads to the formation of π-π stacking interactions. In addition, there are other hydrophobic interactions between the phenylsulfonamide moiety and aromatic residues of the binding site. All these interactions may explain the strong inhibition observed with phenyl-containing compounds, notably compounds 13–15. Moreover, Asn386 is located in proximity to the methylation site and forms two hydrogen bonds with the guanine moiety favoring its right orientation for methylation. Here, fixed on the nitrobenzenesulfonamide core of 13, the chlorine atom forms a halogen bond with Asn386 (Fig. 4 ) [37]. The formation of a double hydrogen bond interaction was observed between the nitro group and Arg310 that normally interacts with the second phosphate group of the triphosphate bond in the cap structure. The docking also suggests that the sulfone group of 13 avoids flexibility of the N-nosyl substituent, thus increasing its orientation into the pocket. This constraint may explain the difference in activity (IC50) and stabilizing effect (T m) between compounds 13 and 15 that contains a methylene group instead of the sulfone. Finally, the common element of all dinucleosides is an adenosine linked to a N-adenosine by the 2′O position. Its contribution is well defined by the formation of intermolecular hydrogen bonds between the adenosine and Gly333 (3′OH), Ile338 (5′OH), Lys336 (N7) and His424 (N1) residues (Fig. 4). All the major interactions maintain 13 in a suitable orientation in the binding site in place of the natural substrate GpppA-RNA. The docking model of 13 is consistent with our inhibition experimental data and high thermal stability of SARS-CoV nsp14 in the presence of these compounds.\nFig. 3 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Amino acids surrounding dinucleoside 13. Hydrogen and halogen bonds are indicated by red dashes. π-π stacking interaction is indicated by red curve. Distances are given in Å. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\nFig. 4 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Contribution of the nitrobenzenesulfonamide core of 13. (B) Contribution of the 2′O linked adenosine of all dinucleosides, including 13. Hydrogen bonds (yellow), halogen bond (green) and π-π stacking interaction (cyan) are represented. (Atoms not involved in protein-ligand interaction are not represented for clarity purpose). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)"}

LitCovid-PubTator

LitCovid-PD-MONDO

{"project":"LitCovid-PD-MONDO","denotations":[{"id":"T84","span":{"begin":200,"end":208},"obj":"Disease"},{"id":"T85","span":{"begin":271,"end":279},"obj":"Disease"},{"id":"T86","span":{"begin":726,"end":734},"obj":"Disease"},{"id":"T87","span":{"begin":1008,"end":1016},"obj":"Disease"},{"id":"T88","span":{"begin":3145,"end":3153},"obj":"Disease"},{"id":"T89","span":{"begin":3249,"end":3257},"obj":"Disease"},{"id":"T90","span":{"begin":3660,"end":3668},"obj":"Disease"}],"attributes":[{"id":"A84","pred":"mondo_id","subj":"T84","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A85","pred":"mondo_id","subj":"T85","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A86","pred":"mondo_id","subj":"T86","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A87","pred":"mondo_id","subj":"T87","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A88","pred":"mondo_id","subj":"T88","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A89","pred":"mondo_id","subj":"T89","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"},{"id":"A90","pred":"mondo_id","subj":"T90","obj":"http://purl.obolibrary.org/obo/MONDO_0005091"}],"text":"To address the molecular bases of N7-MTase nsp14 inhibition by the dinucleosides, we performed computational docking studies of the best inhibitor 13 using Autodock Vina. The docking was based on the SARS-CoV nsp14-nsp10 complex structure solved in presence of SAM [35]. SARS-CoV nsp14 is a bifunctional enzyme carrying RNA cap guanine N7-MTase at the C-terminal domain for mRNA capping (which is not influenced by nsp10) and 3′-5′-exoribonuclease at the N-terminal domain for proofreading. The N7-MTase domain exhibits an original fold and the methyl receptor cap RNA (GpppA-RNA) and SAM bind in proximity in a highly constricted pocket to achieve methyltransfer. The compound 13 was modeled in the SAM binding pocket of the SARS-CoV nsp14 structure (PDB ID: 5C8T [35] \u0026 PDB ID: 5NFY [36]). At first sight, the overlay of the N-adenosine of 13 with the adenosine of SAM bounded structure is suitable (Supporting Information, Fig. S4). More interestingly, the nitrobenzenesulfonamide core of 13 binds into a SARS-CoV nsp14 well known binding site formed by Trp385, Phe401, Tyr420, Phe426 and Phe506 (Fig. 3 , Supporting Information, Fig. S5) [35]. Naturally, the side chains of these amino acids enclose the nucleobase guanine of the cap structure. In this cap-binding site, Phe426 was shown to have the largest influence on the N7-MTase activity, and F426A mutation reduced MTase activity by 50%. With 13, the orientation of the Phe426 residue all around the nitrobenzenesulfonamide leads to the formation of π-π stacking interactions. In addition, there are other hydrophobic interactions between the phenylsulfonamide moiety and aromatic residues of the binding site. All these interactions may explain the strong inhibition observed with phenyl-containing compounds, notably compounds 13–15. Moreover, Asn386 is located in proximity to the methylation site and forms two hydrogen bonds with the guanine moiety favoring its right orientation for methylation. Here, fixed on the nitrobenzenesulfonamide core of 13, the chlorine atom forms a halogen bond with Asn386 (Fig. 4 ) [37]. The formation of a double hydrogen bond interaction was observed between the nitro group and Arg310 that normally interacts with the second phosphate group of the triphosphate bond in the cap structure. The docking also suggests that the sulfone group of 13 avoids flexibility of the N-nosyl substituent, thus increasing its orientation into the pocket. This constraint may explain the difference in activity (IC50) and stabilizing effect (T m) between compounds 13 and 15 that contains a methylene group instead of the sulfone. Finally, the common element of all dinucleosides is an adenosine linked to a N-adenosine by the 2′O position. Its contribution is well defined by the formation of intermolecular hydrogen bonds between the adenosine and Gly333 (3′OH), Ile338 (5′OH), Lys336 (N7) and His424 (N1) residues (Fig. 4). All the major interactions maintain 13 in a suitable orientation in the binding site in place of the natural substrate GpppA-RNA. The docking model of 13 is consistent with our inhibition experimental data and high thermal stability of SARS-CoV nsp14 in the presence of these compounds.\nFig. 3 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Amino acids surrounding dinucleoside 13. Hydrogen and halogen bonds are indicated by red dashes. π-π stacking interaction is indicated by red curve. Distances are given in Å. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\nFig. 4 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Contribution of the nitrobenzenesulfonamide core of 13. (B) Contribution of the 2′O linked adenosine of all dinucleosides, including 13. Hydrogen bonds (yellow), halogen bond (green) and π-π stacking interaction (cyan) are represented. (Atoms not involved in protein-ligand interaction are not represented for clarity purpose). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)"}

LitCovid-PD-CLO

LitCovid-PD-CHEBI

LitCovid-PD-GO-BP

{"project":"LitCovid-PD-GO-BP","denotations":[{"id":"T37","span":{"begin":374,"end":386},"obj":"http://purl.obolibrary.org/obo/GO_0006370"},{"id":"T38","span":{"begin":1497,"end":1506},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T39","span":{"begin":1844,"end":1855},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T40","span":{"begin":1949,"end":1960},"obj":"http://purl.obolibrary.org/obo/GO_0032259"},{"id":"T41","span":{"begin":2088,"end":2097},"obj":"http://purl.obolibrary.org/obo/GO_0009058"},{"id":"T42","span":{"begin":2763,"end":2772},"obj":"http://purl.obolibrary.org/obo/GO_0009058"}],"text":"To address the molecular bases of N7-MTase nsp14 inhibition by the dinucleosides, we performed computational docking studies of the best inhibitor 13 using Autodock Vina. The docking was based on the SARS-CoV nsp14-nsp10 complex structure solved in presence of SAM [35]. SARS-CoV nsp14 is a bifunctional enzyme carrying RNA cap guanine N7-MTase at the C-terminal domain for mRNA capping (which is not influenced by nsp10) and 3′-5′-exoribonuclease at the N-terminal domain for proofreading. The N7-MTase domain exhibits an original fold and the methyl receptor cap RNA (GpppA-RNA) and SAM bind in proximity in a highly constricted pocket to achieve methyltransfer. The compound 13 was modeled in the SAM binding pocket of the SARS-CoV nsp14 structure (PDB ID: 5C8T [35] \u0026 PDB ID: 5NFY [36]). At first sight, the overlay of the N-adenosine of 13 with the adenosine of SAM bounded structure is suitable (Supporting Information, Fig. S4). More interestingly, the nitrobenzenesulfonamide core of 13 binds into a SARS-CoV nsp14 well known binding site formed by Trp385, Phe401, Tyr420, Phe426 and Phe506 (Fig. 3 , Supporting Information, Fig. S5) [35]. Naturally, the side chains of these amino acids enclose the nucleobase guanine of the cap structure. In this cap-binding site, Phe426 was shown to have the largest influence on the N7-MTase activity, and F426A mutation reduced MTase activity by 50%. With 13, the orientation of the Phe426 residue all around the nitrobenzenesulfonamide leads to the formation of π-π stacking interactions. In addition, there are other hydrophobic interactions between the phenylsulfonamide moiety and aromatic residues of the binding site. All these interactions may explain the strong inhibition observed with phenyl-containing compounds, notably compounds 13–15. Moreover, Asn386 is located in proximity to the methylation site and forms two hydrogen bonds with the guanine moiety favoring its right orientation for methylation. Here, fixed on the nitrobenzenesulfonamide core of 13, the chlorine atom forms a halogen bond with Asn386 (Fig. 4 ) [37]. The formation of a double hydrogen bond interaction was observed between the nitro group and Arg310 that normally interacts with the second phosphate group of the triphosphate bond in the cap structure. The docking also suggests that the sulfone group of 13 avoids flexibility of the N-nosyl substituent, thus increasing its orientation into the pocket. This constraint may explain the difference in activity (IC50) and stabilizing effect (T m) between compounds 13 and 15 that contains a methylene group instead of the sulfone. Finally, the common element of all dinucleosides is an adenosine linked to a N-adenosine by the 2′O position. Its contribution is well defined by the formation of intermolecular hydrogen bonds between the adenosine and Gly333 (3′OH), Ile338 (5′OH), Lys336 (N7) and His424 (N1) residues (Fig. 4). All the major interactions maintain 13 in a suitable orientation in the binding site in place of the natural substrate GpppA-RNA. The docking model of 13 is consistent with our inhibition experimental data and high thermal stability of SARS-CoV nsp14 in the presence of these compounds.\nFig. 3 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Amino acids surrounding dinucleoside 13. Hydrogen and halogen bonds are indicated by red dashes. π-π stacking interaction is indicated by red curve. Distances are given in Å. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\nFig. 4 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Contribution of the nitrobenzenesulfonamide core of 13. (B) Contribution of the 2′O linked adenosine of all dinucleosides, including 13. Hydrogen bonds (yellow), halogen bond (green) and π-π stacking interaction (cyan) are represented. (Atoms not involved in protein-ligand interaction are not represented for clarity purpose). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)"}

2_test

{"project":"2_test","denotations":[{"id":"32563813-26159422-29105590","span":{"begin":266,"end":268},"obj":"26159422"},{"id":"32563813-26159422-29105591","span":{"begin":766,"end":768},"obj":"26159422"},{"id":"32563813-29279395-29105592","span":{"begin":786,"end":788},"obj":"29279395"},{"id":"32563813-26159422-29105593","span":{"begin":1143,"end":1145},"obj":"26159422"},{"id":"32563813-15557000-29105594","span":{"begin":2079,"end":2081},"obj":"15557000"}],"text":"To address the molecular bases of N7-MTase nsp14 inhibition by the dinucleosides, we performed computational docking studies of the best inhibitor 13 using Autodock Vina. The docking was based on the SARS-CoV nsp14-nsp10 complex structure solved in presence of SAM [35]. SARS-CoV nsp14 is a bifunctional enzyme carrying RNA cap guanine N7-MTase at the C-terminal domain for mRNA capping (which is not influenced by nsp10) and 3′-5′-exoribonuclease at the N-terminal domain for proofreading. The N7-MTase domain exhibits an original fold and the methyl receptor cap RNA (GpppA-RNA) and SAM bind in proximity in a highly constricted pocket to achieve methyltransfer. The compound 13 was modeled in the SAM binding pocket of the SARS-CoV nsp14 structure (PDB ID: 5C8T [35] \u0026 PDB ID: 5NFY [36]). At first sight, the overlay of the N-adenosine of 13 with the adenosine of SAM bounded structure is suitable (Supporting Information, Fig. S4). More interestingly, the nitrobenzenesulfonamide core of 13 binds into a SARS-CoV nsp14 well known binding site formed by Trp385, Phe401, Tyr420, Phe426 and Phe506 (Fig. 3 , Supporting Information, Fig. S5) [35]. Naturally, the side chains of these amino acids enclose the nucleobase guanine of the cap structure. In this cap-binding site, Phe426 was shown to have the largest influence on the N7-MTase activity, and F426A mutation reduced MTase activity by 50%. With 13, the orientation of the Phe426 residue all around the nitrobenzenesulfonamide leads to the formation of π-π stacking interactions. In addition, there are other hydrophobic interactions between the phenylsulfonamide moiety and aromatic residues of the binding site. All these interactions may explain the strong inhibition observed with phenyl-containing compounds, notably compounds 13–15. Moreover, Asn386 is located in proximity to the methylation site and forms two hydrogen bonds with the guanine moiety favoring its right orientation for methylation. Here, fixed on the nitrobenzenesulfonamide core of 13, the chlorine atom forms a halogen bond with Asn386 (Fig. 4 ) [37]. The formation of a double hydrogen bond interaction was observed between the nitro group and Arg310 that normally interacts with the second phosphate group of the triphosphate bond in the cap structure. The docking also suggests that the sulfone group of 13 avoids flexibility of the N-nosyl substituent, thus increasing its orientation into the pocket. This constraint may explain the difference in activity (IC50) and stabilizing effect (T m) between compounds 13 and 15 that contains a methylene group instead of the sulfone. Finally, the common element of all dinucleosides is an adenosine linked to a N-adenosine by the 2′O position. Its contribution is well defined by the formation of intermolecular hydrogen bonds between the adenosine and Gly333 (3′OH), Ile338 (5′OH), Lys336 (N7) and His424 (N1) residues (Fig. 4). All the major interactions maintain 13 in a suitable orientation in the binding site in place of the natural substrate GpppA-RNA. The docking model of 13 is consistent with our inhibition experimental data and high thermal stability of SARS-CoV nsp14 in the presence of these compounds.\nFig. 3 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Amino acids surrounding dinucleoside 13. Hydrogen and halogen bonds are indicated by red dashes. π-π stacking interaction is indicated by red curve. Distances are given in Å. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\nFig. 4 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Contribution of the nitrobenzenesulfonamide core of 13. (B) Contribution of the 2′O linked adenosine of all dinucleosides, including 13. Hydrogen bonds (yellow), halogen bond (green) and π-π stacking interaction (cyan) are represented. (Atoms not involved in protein-ligand interaction are not represented for clarity purpose). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)"}

LitCovid-sentences

MyTest

{"project":"MyTest","denotations":[{"id":"32563813-26159422-29105590","span":{"begin":266,"end":268},"obj":"26159422"},{"id":"32563813-26159422-29105591","span":{"begin":766,"end":768},"obj":"26159422"},{"id":"32563813-29279395-29105592","span":{"begin":786,"end":788},"obj":"29279395"},{"id":"32563813-26159422-29105593","span":{"begin":1143,"end":1145},"obj":"26159422"},{"id":"32563813-15557000-29105594","span":{"begin":2079,"end":2081},"obj":"15557000"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"To address the molecular bases of N7-MTase nsp14 inhibition by the dinucleosides, we performed computational docking studies of the best inhibitor 13 using Autodock Vina. The docking was based on the SARS-CoV nsp14-nsp10 complex structure solved in presence of SAM [35]. SARS-CoV nsp14 is a bifunctional enzyme carrying RNA cap guanine N7-MTase at the C-terminal domain for mRNA capping (which is not influenced by nsp10) and 3′-5′-exoribonuclease at the N-terminal domain for proofreading. The N7-MTase domain exhibits an original fold and the methyl receptor cap RNA (GpppA-RNA) and SAM bind in proximity in a highly constricted pocket to achieve methyltransfer. The compound 13 was modeled in the SAM binding pocket of the SARS-CoV nsp14 structure (PDB ID: 5C8T [35] \u0026 PDB ID: 5NFY [36]). At first sight, the overlay of the N-adenosine of 13 with the adenosine of SAM bounded structure is suitable (Supporting Information, Fig. S4). More interestingly, the nitrobenzenesulfonamide core of 13 binds into a SARS-CoV nsp14 well known binding site formed by Trp385, Phe401, Tyr420, Phe426 and Phe506 (Fig. 3 , Supporting Information, Fig. S5) [35]. Naturally, the side chains of these amino acids enclose the nucleobase guanine of the cap structure. In this cap-binding site, Phe426 was shown to have the largest influence on the N7-MTase activity, and F426A mutation reduced MTase activity by 50%. With 13, the orientation of the Phe426 residue all around the nitrobenzenesulfonamide leads to the formation of π-π stacking interactions. In addition, there are other hydrophobic interactions between the phenylsulfonamide moiety and aromatic residues of the binding site. All these interactions may explain the strong inhibition observed with phenyl-containing compounds, notably compounds 13–15. Moreover, Asn386 is located in proximity to the methylation site and forms two hydrogen bonds with the guanine moiety favoring its right orientation for methylation. Here, fixed on the nitrobenzenesulfonamide core of 13, the chlorine atom forms a halogen bond with Asn386 (Fig. 4 ) [37]. The formation of a double hydrogen bond interaction was observed between the nitro group and Arg310 that normally interacts with the second phosphate group of the triphosphate bond in the cap structure. The docking also suggests that the sulfone group of 13 avoids flexibility of the N-nosyl substituent, thus increasing its orientation into the pocket. This constraint may explain the difference in activity (IC50) and stabilizing effect (T m) between compounds 13 and 15 that contains a methylene group instead of the sulfone. Finally, the common element of all dinucleosides is an adenosine linked to a N-adenosine by the 2′O position. Its contribution is well defined by the formation of intermolecular hydrogen bonds between the adenosine and Gly333 (3′OH), Ile338 (5′OH), Lys336 (N7) and His424 (N1) residues (Fig. 4). All the major interactions maintain 13 in a suitable orientation in the binding site in place of the natural substrate GpppA-RNA. The docking model of 13 is consistent with our inhibition experimental data and high thermal stability of SARS-CoV nsp14 in the presence of these compounds.\nFig. 3 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Amino acids surrounding dinucleoside 13. Hydrogen and halogen bonds are indicated by red dashes. π-π stacking interaction is indicated by red curve. Distances are given in Å. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\nFig. 4 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID: 5C8T, resolution 3.2 Å). (A) Contribution of the nitrobenzenesulfonamide core of 13. (B) Contribution of the 2′O linked adenosine of all dinucleosides, including 13. Hydrogen bonds (yellow), halogen bond (green) and π-π stacking interaction (cyan) are represented. (Atoms not involved in protein-ligand interaction are not represented for clarity purpose). (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)"}

PMC:7291971 / 28114-32284 JSONTXT

Annnotations TAB JSON ListView MergeView

PMC:7291971 / 28114-32284 JSON TXT