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

0495169 - ÚMG 2019 RIV DE eng J - Journal Article
Pecina, A. - Brynda, Jiří - Vrzal, L. - Gnanasekaran, R. - Hořejší, Magdalena - Eyrilmez, S.M. - Řezáč, J. - Lepšík, M. - Řezáčová, Pavlína - Hobza, P. - Majer, P. - Veverka, V. - Fanfrlik, J.
Ranking Power of the SQM/COSMO Scoring Function on Carbonic AnhydraseII-Inhibitor Complexes.
ChemPhysChem. Roč. 19, č. 7 (2018), s. 873-879. ISSN 1439-4235. E-ISSN 1439-7641
Institutional support: RVO:68378050
Keywords : binding affinities * crystallography * lead optimization * quantum mechanics * scoring function
OECD category: Biochemistry and molecular biology
Impact factor: 3.077, year: 2018

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 anhydraseII through Zn2+ in the active site. This new dataset consists of the high-resolution (1.1-1.4 angstrom) 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.
Permanent Link: http://hdl.handle.net/11104/0288179