Download MendeleyRanking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II-Inhibitor Complexes.
Pecina, A., Brynda, J., Vrzal, L., Gnanasekaran, R., Horejsi, M., Eyrilmez, S.M., Rezac, J., Lepsik, M., Rezacova, P., Hobza, P., Majer, P., Veverka, V., Fanfrlik, J.(2018) Chemphyschem 19: 873-879
- PubMed: 29316128
- DOI: https://doi.org/10.1002/cphc.201701104
- Primary Citation of Related Structures:
5NXG, 5NXI, 5NXM, 5NXO, 5NXP, 5NXV, 5NXW, 5NY1, 5NY3, 5NY6, 5NYA - PubMed Abstract:
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 2+ 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 i ) 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 2 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.
Organizational Affiliation:
Institute of Organic Chemistry and Biochemistry of the, Czech Academy of Sciences, Flemingovo nam. 2, 16610, Prague 6, Czech Republic.
