We chose Glide as the docking software, due to its superiority over mainstream docking software on the DEKOIS2.0 set . First, we investigate the impact of explicit calculation of ∆H using the PM6/COSMO with the D3H4X corrections on P-L scoring, but also the effect of inclusion of explicitly calculated ligand conformational entropy. Then we test various SQM/MM optimization schemes to study the effect of SQM part size on both the final 3D structure and P-L scoring. Upon that we establish an optimal P-L scoring protocol balancing performance and computational time, which we implemented to score a panel of 17 diverse targets using a diverse set of ligands/decoys from DEKOIS 2.0 (40 actives / 1200 decoys), resulting in 1.5 million P-L complexes and 1.2 million CPU hours. To our knowledge, this is the most systematic and extensive application of SQM to VS.