tetano
Editor, Senior Moderator
Virology
. 2026 Feb 24:618:110845.
doi: 10.1016/j.virol.2026.110845. Online ahead of print.
Naturally occurring C-C and C-O-C-linked biflavonoids as potential inhibitors of the SARS-CoV-2 main protease (M[SUP]pro[/SUP])
Suvankar Karmakar[SUP] 1 [/SUP], Sk Aftabul Alam[SUP] 2 [/SUP], Samiran Mondal[SUP] 3 [/SUP]
Affiliations
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M[SUP]pro[/SUP]) is indispensable for viral replication and remains a validated antiviral drug target. Naturally occurring biflavonoids, particularly those with C-C and C-O-C interflavonoid linkages, have gained attention due to their structural diversity and reported antiviral potential. In this study, an integrated in silico approach was employed to investigate the inhibitory potential of representative biflavonoids against SARS-CoV-2 M[SUP]pro[/SUP]. A curated library of C-C- and C-O-C-linked biflavonoids was initially screened using molecular docking within the catalytic pocket of M[SUP]pro[/SUP] (PDB ID: 6LU7), followed by density functional theory (DFT) calculations to evaluate electronic properties and chemical reactivity. Molecular dynamics simulations (MDS) were performed to assess the structural stability of the ligand-M[SUP]pro[/SUP] complexes, while binding free energies were estimated using the MM/PBSA method. Principal component analysis (PCA) and free energy landscape (FEL) analyses were applied to characterize essential motions and conformational stability during the simulations. Key interactions with the catalytic dyad (His41 and Cys145) and surrounding residues, including Glu166, His163, and Gly143, were consistently observed. Comparative analyses revealed that C-C-linked biflavonoids, particularly amentoflavone and robustaflavone, exhibited more favourable binding affinities and dynamic stability than C-O-C-linked counterparts such as hinokiflavone and ochnaflavone, although both classes demonstrated inhibitory potential. Drug-likeness and pharmacokinetic properties were evaluated using ADMET predictions and Molinspiration analysis, while toxicity assessment via ProTox-3 indicated low predicted toxicity for the top-ranked compounds. Overall, these findings suggest that naturally occurring biflavonoids, C-C- and C-O-C-linked scaffolds, represent promising leads for SARS-CoV-2 M[SUP]pro[/SUP] inhibition and merit further experimental validation.
Keywords: Biflavonoids; C-C and C-O-C linkages; DFT; In silico drug discovery; Main protease (M(pro)); Molecular docking; Molecular dynamics simulation; SARS-CoV-2.
. 2026 Feb 24:618:110845.
doi: 10.1016/j.virol.2026.110845. Online ahead of print.
Naturally occurring C-C and C-O-C-linked biflavonoids as potential inhibitors of the SARS-CoV-2 main protease (M[SUP]pro[/SUP])
Suvankar Karmakar[SUP] 1 [/SUP], Sk Aftabul Alam[SUP] 2 [/SUP], Samiran Mondal[SUP] 3 [/SUP]
Affiliations
- PMID: 41763003
- DOI: 10.1016/j.virol.2026.110845
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (M[SUP]pro[/SUP]) is indispensable for viral replication and remains a validated antiviral drug target. Naturally occurring biflavonoids, particularly those with C-C and C-O-C interflavonoid linkages, have gained attention due to their structural diversity and reported antiviral potential. In this study, an integrated in silico approach was employed to investigate the inhibitory potential of representative biflavonoids against SARS-CoV-2 M[SUP]pro[/SUP]. A curated library of C-C- and C-O-C-linked biflavonoids was initially screened using molecular docking within the catalytic pocket of M[SUP]pro[/SUP] (PDB ID: 6LU7), followed by density functional theory (DFT) calculations to evaluate electronic properties and chemical reactivity. Molecular dynamics simulations (MDS) were performed to assess the structural stability of the ligand-M[SUP]pro[/SUP] complexes, while binding free energies were estimated using the MM/PBSA method. Principal component analysis (PCA) and free energy landscape (FEL) analyses were applied to characterize essential motions and conformational stability during the simulations. Key interactions with the catalytic dyad (His41 and Cys145) and surrounding residues, including Glu166, His163, and Gly143, were consistently observed. Comparative analyses revealed that C-C-linked biflavonoids, particularly amentoflavone and robustaflavone, exhibited more favourable binding affinities and dynamic stability than C-O-C-linked counterparts such as hinokiflavone and ochnaflavone, although both classes demonstrated inhibitory potential. Drug-likeness and pharmacokinetic properties were evaluated using ADMET predictions and Molinspiration analysis, while toxicity assessment via ProTox-3 indicated low predicted toxicity for the top-ranked compounds. Overall, these findings suggest that naturally occurring biflavonoids, C-C- and C-O-C-linked scaffolds, represent promising leads for SARS-CoV-2 M[SUP]pro[/SUP] inhibition and merit further experimental validation.
Keywords: Biflavonoids; C-C and C-O-C linkages; DFT; In silico drug discovery; Main protease (M(pro)); Molecular docking; Molecular dynamics simulation; SARS-CoV-2.