Screening database preparation. The Enamine REAL lead-like (ERLL) library, containing a total of 1.56 billion compounds (March 2021), was selected for the giga-scale screening. All included compounds have lead-like properties, with molecular weight ≤460 Da, SlogP -4.0 to 4.2, number of hydrogen bond acceptors <10 and donors <5, number of ring systems ≤4 and rotatable bonds ≤10. The library was obtained in ChemAxon extended SMILES format and converted to regular SMILES using RDKit v2021.03.5, retaining the stereochemical information of the compounds where applicable. To reduce the variation in docking times between different subsets, compound order first was randomized, and SMILES were then evenly divided into 20 subsets. Ligand 3D structure preparation for docking was carried out with Schrödinger LigPrep (Schrödinger Suite 2021-1). Up to 8 tautomers per compound and 4 stereoisomers per tautomer for a target pH of 7.0 ± 1.5 were generated and compound geometries were energy-minimized with the OPLS_2005 forcefield.