LitCovid-sentences  

PMC:7291971 / 28114-32284 JSONTXT 11 Projects

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Id Subject Object Predicate Lexical cue
T202 0-170 Sentence denotes 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.
T203 171-270 Sentence denotes The docking was based on the SARS-CoV nsp14-nsp10 complex structure solved in presence of SAM [35].
T204 271-490 Sentence denotes 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.
T205 491-664 Sentence denotes 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.
T206 665-759 Sentence denotes The compound 13 was modeled in the SAM binding pocket of the SARS-CoV nsp14 structure (PDB ID:
T207 760-779 Sentence denotes 5C8T [35] & PDB ID:
T208 780-791 Sentence denotes 5NFY [36]).
T209 792-935 Sentence denotes At first sight, the overlay of the N-adenosine of 13 with the adenosine of SAM bounded structure is suitable (Supporting Information, Fig. S4).
T210 936-1147 Sentence denotes 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].
T211 1148-1248 Sentence denotes Naturally, the side chains of these amino acids enclose the nucleobase guanine of the cap structure.
T212 1249-1397 Sentence denotes 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%.
T213 1398-1536 Sentence denotes With 13, the orientation of the Phe426 residue all around the nitrobenzenesulfonamide leads to the formation of π-π stacking interactions.
T214 1537-1670 Sentence denotes In addition, there are other hydrophobic interactions between the phenylsulfonamide moiety and aromatic residues of the binding site.
T215 1671-1795 Sentence denotes All these interactions may explain the strong inhibition observed with phenyl-containing compounds, notably compounds 13–15.
T216 1796-1961 Sentence denotes 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.
T217 1962-2083 Sentence denotes Here, fixed on the nitrobenzenesulfonamide core of 13, the chlorine atom forms a halogen bond with Asn386 (Fig. 4 ) [37].
T218 2084-2286 Sentence denotes 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.
T219 2287-2437 Sentence denotes The docking also suggests that the sulfone group of 13 avoids flexibility of the N-nosyl substituent, thus increasing its orientation into the pocket.
T220 2438-2612 Sentence denotes 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.
T221 2613-2722 Sentence denotes Finally, the common element of all dinucleosides is an adenosine linked to a N-adenosine by the 2′O position.
T222 2723-2908 Sentence denotes 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).
T223 2909-3038 Sentence denotes All the major interactions maintain 13 in a suitable orientation in the binding site in place of the natural substrate GpppA-RNA.
T224 3039-3195 Sentence denotes 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.
T225 3196-3272 Sentence denotes Fig. 3 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID:
T226 3273-3342 Sentence denotes 5C8T, resolution 3.2 Å). (A) Amino acids surrounding dinucleoside 13.
T227 3343-3450 Sentence denotes Hydrogen and halogen bonds are indicated by red dashes. π-π stacking interaction is indicated by red curve.
T228 3451-3606 Sentence denotes 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.)
T229 3607-3683 Sentence denotes Fig. 4 Modeling results in the SAM binding pocket of SARS-CoV nsp14 (PDB ID:
T230 3684-3849 Sentence denotes 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.
T231 3850-4170 Sentence denotes 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.)