In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs
Aim: COVID 19 continues to be a major health concern. RNA dependent RNA polymerase of SARS-CoV-2 which is crucial for replication is therefore a potential drug target. Methodology: Based on experimental structures of RdRp from SARS-CoV-2, computational models were generated of its homologs from SARS...
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Elsevier
2025-06-01
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| Series: | Biochemistry and Biophysics Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405580825000627 |
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| author | Shamiya Anwar Kizhakkiniyakath Tejaswini Choudhury Madhan Vishal Rajan Sagar Rathee Basant Meena Gururao Hariprasad |
| author_facet | Shamiya Anwar Kizhakkiniyakath Tejaswini Choudhury Madhan Vishal Rajan Sagar Rathee Basant Meena Gururao Hariprasad |
| author_sort | Shamiya Anwar Kizhakkiniyakath |
| collection | DOAJ |
| description | Aim: COVID 19 continues to be a major health concern. RNA dependent RNA polymerase of SARS-CoV-2 which is crucial for replication is therefore a potential drug target. Methodology: Based on experimental structures of RdRp from SARS-CoV-2, computational models were generated of its homologs from SARS-CoV-1, MERS and Bat. SARS CoV-2 RdRp was used for virtual screening at nucleotide binding site with molecule from COCONUT Natural Products database using Glide. Complexes with the top inhibitor molecule were modelled using Discovery Studio and Desmond suite of programs. Results: SARS-CoV-2 RdRp has a minimum of 80 % sequence similarity with its homologs, with the secondary structural elements, catalytic residues and metal binding residues being conserved. Certain residue variations in SARS-CoV-2 RdRp seems to be responsible for the stability of the enzyme. Docking and simulation studies showed that a flavonoid molecule with Coconut ID: CNP0127177.0 (HHF318) has binding affinity in low nano-molar range against RdRp from SARS-CoV-2 which was comparable or better than currently used inhibitors. This affinity stems from cationic-π with Arg555, and π-stacking interactions with a nucleobase of RNA. Molecule also engages with other residues that are crucial for its functions. This flavonoid molecule has similar physio-chemical properties like ATP towards SARS-CoV-2 RdRp, and has low potency for human ATP binding proteins. Conclusion: HHF318 is a potential inhibitor of SARS-CoV-2 RdRp with good potency, specificity and pharmacokinetic properties for it to be developed as a drug candidate for COVID19. |
| format | Article |
| id | doaj-art-2bdf54aed1b341e3b2a8d94b5f2f6b27 |
| institution | DOAJ |
| issn | 2405-5808 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
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| series | Biochemistry and Biophysics Reports |
| spelling | doaj-art-2bdf54aed1b341e3b2a8d94b5f2f6b272025-08-20T03:22:35ZengElsevierBiochemistry and Biophysics Reports2405-58082025-06-014210197510.1016/j.bbrep.2025.101975In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologsShamiya Anwar Kizhakkiniyakath0Tejaswini Choudhury1Madhan Vishal Rajan2Sagar Rathee3Basant Meena4Gururao Hariprasad5Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, IndiaDepartment of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, IndiaCorresponding author.; Department of Biophysics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, IndiaAim: COVID 19 continues to be a major health concern. RNA dependent RNA polymerase of SARS-CoV-2 which is crucial for replication is therefore a potential drug target. Methodology: Based on experimental structures of RdRp from SARS-CoV-2, computational models were generated of its homologs from SARS-CoV-1, MERS and Bat. SARS CoV-2 RdRp was used for virtual screening at nucleotide binding site with molecule from COCONUT Natural Products database using Glide. Complexes with the top inhibitor molecule were modelled using Discovery Studio and Desmond suite of programs. Results: SARS-CoV-2 RdRp has a minimum of 80 % sequence similarity with its homologs, with the secondary structural elements, catalytic residues and metal binding residues being conserved. Certain residue variations in SARS-CoV-2 RdRp seems to be responsible for the stability of the enzyme. Docking and simulation studies showed that a flavonoid molecule with Coconut ID: CNP0127177.0 (HHF318) has binding affinity in low nano-molar range against RdRp from SARS-CoV-2 which was comparable or better than currently used inhibitors. This affinity stems from cationic-π with Arg555, and π-stacking interactions with a nucleobase of RNA. Molecule also engages with other residues that are crucial for its functions. This flavonoid molecule has similar physio-chemical properties like ATP towards SARS-CoV-2 RdRp, and has low potency for human ATP binding proteins. Conclusion: HHF318 is a potential inhibitor of SARS-CoV-2 RdRp with good potency, specificity and pharmacokinetic properties for it to be developed as a drug candidate for COVID19.http://www.sciencedirect.com/science/article/pii/S2405580825000627SARS-CoV-2RNA dependent RNA polymeraseStructure based drug screeningEnzyme inhibitionFlavonoid molecule |
| spellingShingle | Shamiya Anwar Kizhakkiniyakath Tejaswini Choudhury Madhan Vishal Rajan Sagar Rathee Basant Meena Gururao Hariprasad In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs Biochemistry and Biophysics Reports SARS-CoV-2 RNA dependent RNA polymerase Structure based drug screening Enzyme inhibition Flavonoid molecule |
| title | In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs |
| title_full | In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs |
| title_fullStr | In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs |
| title_full_unstemmed | In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs |
| title_short | In silico studies to understand the interactions of flavonoid inhibitor with nsp12-RNA dependent RNA polymerase of SARS-CoV-2 and its homologs |
| title_sort | in silico studies to understand the interactions of flavonoid inhibitor with nsp12 rna dependent rna polymerase of sars cov 2 and its homologs |
| topic | SARS-CoV-2 RNA dependent RNA polymerase Structure based drug screening Enzyme inhibition Flavonoid molecule |
| url | http://www.sciencedirect.com/science/article/pii/S2405580825000627 |
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