Moreover, by looking at the available PDB structures of those 4 receptors and the respective publications, we discovered strong ligand-induced fit effects, flexible loops, alternative protonation states of catalytic residues, and ambiguous presence of co-factors or ions. Hence the poor performance of PM6/COSMO and Glide SP in these datasets using a single receptor structure. In contrast, hybrid ML-based SFs like SQM-ML are less dependent on receptor conformational changes and thus more robust. We showcase the SARS-HCoV, for which both Glide SP and PM6/COSMO scored below the baseline. First and foremost, we removed the Zinc ion as it was blocking the entrance of ligands to the active site and hence is absent in most PDB structures (e.g. 1WOF, 2GTB, 2ZU4, 7LCQ). Other factors compromising the performance can be that the binding site is open and exposed to the solvent (Figure Figure ), the catalytic His41 assumes alternative protonation states, 61 or ligand-induced fit effect (Figure ). The results of the structure analysis of the other 3 receptors are reported in the Supporting Material, Figures S12, S13, S14. From a practical point of view, the current scoring pipeline consists of many individual steps (compound preparation for docking, docking, compound SQM geometry optimization, AM1-bcc charge calculation, MM energy minimization, SQM optimization, and scoring) conducted by various software. As such, in each step, many structures are discarded due to incompatibility or failures, which eventually reduces the total number of compounds that are scored (Table ). The most frequent conflicts occur due to wrongly estimated net charges of the ligand, the protein, or the binding cavity in the case of SQM/MM optimization of protein residues. Then follow the problems with missing GAFF2 force field parameters for some chemical groups, SDF ↔ M OL2 file type conversions that result in wrong bond or atom types, sanitization errors, etc. Devising heuristics to tackle the most frequently occurring problems and thus increase the productivity of the pipeline is in our immediate goals.