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Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II–Inhibitor Complexes
Author(s) -
Pecina Adam,
Brynda Jiří,
Vrzal Lukáš,
Gnanasekaran Ramachandran,
Hořejší Magdalena,
Eyrilmez Saltuk M.,
Řezáč Jan,
Lepšík Martin,
Řezáčová Pavlína,
Hobza Pavel,
Majer Pavel,
Veverka Václav,
Fanfrlík Jindřich
Publication year - 2018
Publication title -
chemphyschem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.016
H-Index - 140
eISSN - 1439-7641
pISSN - 1439-4235
DOI - 10.1002/cphc.201701104
Subject(s) - chemistry , virtual screening , carbonic anhydrase ii , solvation , cosmo rs , aryl , ligand (biochemistry) , computational chemistry , ranking (information retrieval) , carbonic anhydrase , solvent , computer science , molecular dynamics , machine learning , organic chemistry , alkyl , enzyme , biochemistry , ionic liquid , receptor , catalysis
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.