For hesperidin (Figure ) four of the five rings are buried deep in the binding pocket, with the hydrophilic terminal sugar ring being exposed to the solvent. There are networks of hydrogens bond between the active site residues and the donor and acceptor groups on most repurposed drugs, especially for aminoquinuride and rutin. Supplementary Table lists the key interactions between the top screening hits and the active site of the helicase. The 6 residues in helicase binding pocket Lys288, Ser289, Asp374, Glu375, Gln404, Arg567 are crucial for ATP hydrolysis and all screened drugs interacted strongly with these residues. These molecularlevel interactions involved in binding the drugs at ATP binding site of the SARS-Cov-2 helicase enzyme were investigated to decipher the key chemical forces crucial for intermolecular binding and stability of complexes. Cabetogravir, dicoumarol, fexofenadine, epirubicin, antrafenine, aminoquinuride, aprepitant, RSV-604 all formed strong hydrogen bonds with residues in the ATP-binding site at Rec1A domain. Aprepitant also formed π-stacking (Try541) and π-cation (Lys320) interactions with nsp-13. Antrafenine and aprepitant form halogen bonds with Ile399 and Asp374 respectively. For the antiviral integrase drug, carbogravir (Figure ), the tricyclic ring is buried deep within the active site of the helicase. Again, the abundant hydrogen bond donors and acceptors on the polycyclic moiety form hydrogen bonds with the binding site residues of the helicase. The vasopressin inhibitor, canivaptan (Figure ), buries its hydrophilic nitrogen-rich heterocyclic rings deep within the binding cleft, forming a range of hydrogen bonds with active site residues. Aprepitant (NK1 antagonist) buries the morpholino ether moiety in the hydrophilic pocket and the hydrophobic bis trifluoromethyl substituted ring even deeper into this pocket. The environment mismatch is compensated by the favourable π-stacking and π-cation interactions referred to above.