Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain
We hypothesize that in silico structural biology approaches can discover novel drug binding sites for RNA-dependent-RNA-polymerases (RdRp) of positive sense single-strand RNA (ss(+)RNA) virus species. RdRps have a structurally conserved active site with seven motifs (A to G), despite low sequence si...
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-10-01
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| Series: | BioMedInformatics |
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| Online Access: | https://www.mdpi.com/2673-7426/3/4/55 |
| _version_ | 1827575506285887488 |
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| author | Aparna S. Gana James N. Baraniuk |
| author_facet | Aparna S. Gana James N. Baraniuk |
| author_sort | Aparna S. Gana |
| collection | DOAJ |
| description | We hypothesize that in silico structural biology approaches can discover novel drug binding sites for RNA-dependent-RNA-polymerases (RdRp) of positive sense single-strand RNA (ss(+)RNA) virus species. RdRps have a structurally conserved active site with seven motifs (A to G), despite low sequence similarity. We refined this architecture further to describe a conserved structural domain consisting of motifs A, B, C and F. These motifs were used to realign 24 RdRp structures in an innovative manner to search for novel drug binding sites. The aligned motifs from the enzymes were then docked with 833 FDA-approved drugs (Set 1) and 85 FDA-approved antivirals (Set 2) using the Molecular Operating Environment (MOE) docking 2020.09 software. Sirolimus (rapamycin), an immunosuppressant that targets the mammalian mTOR pathway, was one of the top ten drugs for all 24 RdRp proteins. The sirolimus docking site was in the nucleotide triphosphate entry tunnel between motifs A and F but distinct from the active site in motif C. This original finding supports our hypothesis that structural biology approaches based on RdRp motifs that are conserved across evolution can define new drug binding locations and infer potential broad-spectrum inhibitors for SARS-CoV-2 and other ss(+)RNA viruses. |
| first_indexed | 2024-03-08T20:58:04Z |
| format | Article |
| id | doaj.art-c99de011273941e68df96f4e27dce55c |
| institution | Directory Open Access Journal |
| issn | 2673-7426 |
| language | English |
| last_indexed | 2024-03-08T20:58:04Z |
| publishDate | 2023-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | BioMedInformatics |
| spelling | doaj.art-c99de011273941e68df96f4e27dce55c2023-12-22T13:55:24ZengMDPI AGBioMedInformatics2673-74262023-10-013488590710.3390/biomedinformatics3040055Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) DomainAparna S. Gana0James N. Baraniuk1College of Arts and Sciences, University of Virginia, 402 Balz Dobie, Charlottesville, VA 22904-3104, USADivision of Rheumatology, Immunology and Allergy, Department of Medicine, Georgetown University Medical Center, 3900 Reservoir Rd NW, Washington, DC 20007, USAWe hypothesize that in silico structural biology approaches can discover novel drug binding sites for RNA-dependent-RNA-polymerases (RdRp) of positive sense single-strand RNA (ss(+)RNA) virus species. RdRps have a structurally conserved active site with seven motifs (A to G), despite low sequence similarity. We refined this architecture further to describe a conserved structural domain consisting of motifs A, B, C and F. These motifs were used to realign 24 RdRp structures in an innovative manner to search for novel drug binding sites. The aligned motifs from the enzymes were then docked with 833 FDA-approved drugs (Set 1) and 85 FDA-approved antivirals (Set 2) using the Molecular Operating Environment (MOE) docking 2020.09 software. Sirolimus (rapamycin), an immunosuppressant that targets the mammalian mTOR pathway, was one of the top ten drugs for all 24 RdRp proteins. The sirolimus docking site was in the nucleotide triphosphate entry tunnel between motifs A and F but distinct from the active site in motif C. This original finding supports our hypothesis that structural biology approaches based on RdRp motifs that are conserved across evolution can define new drug binding locations and infer potential broad-spectrum inhibitors for SARS-CoV-2 and other ss(+)RNA viruses.https://www.mdpi.com/2673-7426/3/4/55RNA-dependent-RNA-polymerase (RdRp)sirolimusrapamycinsingle-stranded positive-sense RNA virusesss(+)RNAevolutionarily conserved region |
| spellingShingle | Aparna S. Gana James N. Baraniuk Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain BioMedInformatics RNA-dependent-RNA-polymerase (RdRp) sirolimus rapamycin single-stranded positive-sense RNA viruses ss(+)RNA evolutionarily conserved region |
| title | Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain |
| title_full | Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain |
| title_fullStr | Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain |
| title_full_unstemmed | Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain |
| title_short | Identification of a New Drug Binding Site in the RNA-Dependent-RNA-Polymerase (RdRp) Domain |
| title_sort | identification of a new drug binding site in the rna dependent rna polymerase rdrp domain |
| topic | RNA-dependent-RNA-polymerase (RdRp) sirolimus rapamycin single-stranded positive-sense RNA viruses ss(+)RNA evolutionarily conserved region |
| url | https://www.mdpi.com/2673-7426/3/4/55 |
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