Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II-Inhibitor Complexes

Chemphyschem. 2018 Apr 5;19(7):873-879. doi: 10.1002/cphc.201701104. Epub 2018 Feb 19.


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 Zn2+ in the active site. This new dataset consists of the high-resolution (1.1-1.4 Å) crystal structures and experimentally determined inhibitory constant (Ki ) 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 R2 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.

Keywords: binding affinities; crystallography; lead optimization; quantum mechanics; scoring function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carbonic Anhydrase II / chemistry
  • Carbonic Anhydrase II / metabolism*
  • Carbonic Anhydrase Inhibitors / chemistry
  • Carbonic Anhydrase Inhibitors / metabolism*
  • Drug Design
  • Ligands
  • Models, Chemical
  • Molecular Docking Simulation
  • Protein Binding
  • Quantum Theory
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism*


  • Carbonic Anhydrase Inhibitors
  • Ligands
  • Sulfonamides
  • Carbonic Anhydrase II