b) Similarity matching. Because the molecules generated by our program are built from scratch, they may be different from the standard available molecules. Sometimes it could also be away from known synthetic routes, and devising synthetic methods for these new molecules might be expensive and timeconsuming. Most importantly, our de novo molecules are not screened for ADMET (adsorption, distribution, metabolism, excretion, and toxicity) criteria required to be a drug. Therefore, we augmented our list of strong binders (based on the interaction energy mentioned before) with known drug molecules with similar chemical structures, with the assumption that molecules with similar structures would exhibit similar functions, as shown in our previous study . Thus, we mapped our molecules to approved or investigational (repurpose) drugs from the DrugBank 42 database with a Tanimoto similarity score of 0.4 or more, which has been shown to be significant . We screened the drug molecules selected based on structural similarity to our high scoring de novo molecules further for docking scores using AutoDock Vina version 1.1.2 to ensure the preliminary idea of their binding strength. A box centered near the mid-point of the Asn691 and Cys622 side chains was created with dimensions 32.6 Å×33.3 Å×36.5 Å. The docking score of the molecules is provided in Table of the Supporting Information (SI). The chemical structures of both de novo and repurpose drugs are shown in Fig. . c) Free energy validation. Finally, we calculated the binding free energy for each of these molecules (selected based on strong interaction energy for de novo molecules and high docking score for structurally similar drug molecules) using allatom, explicit water metadynamics simulations as described later in this article. i. Forcefield generation: Following the guideline of General Amber Force Field (GAFF) , we optimized all the molecules using Hartree-Fock (HF) theory with 6-31G* basis set using Gaussian 09 software . We then used the antechamber module of AMBER18 for the RESP charge calculation of drug atoms. For protein, we used AMBER99SB force field. The topology and coordinates were then converted into the GROMACS format by using a python script acpype.py (available at ) .