The helicase is 603 long amino acid protein and has a shape of a triangular pyramid that is divided into five sections, a zinc-binding domain (ZBD) which is attached to two Rec-A domains (Rec1A and Rec2A) and a Rec1B domain via a stalk domain (Figure ). The hydrolytic activity is attributed to six key residues (Lys288, Ser289, Asp374, Glu375, Gln404, Arg567 found within the cleft between the 1A and 2A domains at the base. These residues are located at the active site of SARS-CoV-2 helicase enzyme. (Figure ). The binding pocket of helicase has a volume of 325 Å 3 and an area of 420Å 2 . Figure . Key active site residues for helicase bound to the AMP-PNP Mg2+ complex (left) and the AMP-PNP complex (right). Used with permission from Newman et al. The workflow for calculating the relative binding affinities of drugs for the helicase binding pocket is summarized in Supplementary Figure . Autodock Vina docking followed by MD simulation of the top candidates provides improved predictions of relative binding affinities compared to docking alone. For example, significant improvement in protein-ligand docking results was shown by subsequent highthroughput MD simulations .