Beschreibung:
<jats:title>Abstract</jats:title><jats:p>Accurate prediction of protein–ligand binding affinities is essential for hit‐to‐lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn<jats:sup>2+</jats:sup> in the active site. This new dataset consists of the high‐resolution (1.1–1.4 Å) crystal structures and experimentally determined inhibitory constant (<jats:italic>K</jats:italic><jats:sub>i</jats:sub>) values. It allows for evaluation of the common approximations, such as representing the solvent implicitly or by using a single target conformation combined with a set of ligand docking poses. SQM/COSMO attained a good correlation of <jats:italic>R</jats:italic><jats:sup><jats:italic>2</jats:italic></jats:sup> of 0.56–0.77 with the experimental inhibitory activities, benefiting from careful handling of both noncovalent interactions (e.g. charge transfer) and solvation. This proof‐of‐concept study of SQM/COSMO ranking for metalloprotein–ligand systems demonstrates its potential for hit‐to‐lead applications.</jats:p>