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 in the active site. This new dataset consists of the high-resolution (1.1-1.4 Å) crystal structures and experimentally determined inhibitory constant (K ) 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 R 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.

The weakly coordinating binary macropolyhedral anion closo,closo- [B 21 H 18 ]À (B21; D 3h symmetry) has been synthesized using a simplified strategy compared to that in the literature. While gas-phase complexes of B21 with b-and c-cyclodextrin (CD) were detected using ESI FT-ICR spectrometric measurements, a-CD did not bind to the B21 guest. This spectroscopic evidence has been interpreted using quantum-chemical