a) Screening of DeNovo molecule. Our de novo program generated a total of 5375 molecules, with a target of picking at least 160 molecules of the number of heavy atoms ranging between 11 and 50. Molecules with more than 43 heavy atoms, however, could not be generated owing to the limited size of the active site. The strongest interaction energy (de novo score) was at -150.6 kJ/mol, and the weakest was at -22.1 kJ/mol. The distribution of interaction energies to the active site of RdRp is shown in Fig. of the Supplementary Information (SI). We took the top molecules for the calculation of free energy using well-tempered metadynamics. b) Free energy studies of RTP. The multi-dimensional free energy surface of RTP is shown in the Fig. . The minimum free energy path connecting the bound minima state to the unbound state is shown by black dotted lines in the Fig. . The unbinding proceeds with an increase in the CVs 𝑋 and 𝜃. A 2D representation of the RTP molecule with the possible stabilizing interaction in the minima with the residues of protein is shown in Fig. . The top view of the RTP bound RdRp at its minima state is shown in the Fig. . Structures of relevant intermediate states of RdRp-RTP complex along the minimum free energy unbinding path are shown in the Fig. in accordance with the free energy profile RTP (States I to VI in Fig. ). The free energy of RTP was found to be -7.1 kcal/mol, closely matching the reported results. In the minima, the triphosphate of the RTP molecule is found to be stabilized by the hydrogen bond with Lys545 residue of the RdRp, while the other terminal end is found to be stabilized by the hydrogen bond by Asn496 (Fig. ). The core of RTP is stabilized by the hydrophobic interactions from the residues Asn497, Leu498, Asp499, and Lys500. The minimum free energy of the RTP is found to be located at the known hotspot region (yellow region shown in Fig. ). RdRp core structure also consists of architecture containing finger and palm sub-domains which are essential in substrate recognition. After the formation of possible interactions in the hotspot region (state I to III), the RTP moves towards the finger sub-region by cyan colour) as shown by the states IV and V in Fig. . Finally, the departure of the molecule to the accessible solvent region is initiated from this finger subregion. c) Free energy studies of de novo molecules and known repurposable molecules. As the objective of our study was to find the molecules having better binding affinity than RTP, we followed the same free energy validation protocol for selected de novo and repurpose drugs as discussed in the methods section.