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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00490170" target="_blank" >RIV/61388963:_____/18:00490170 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68378050:_____/18:00495169 RIV/61989592:15310/18:73591477

Výsledek na webu

<a href="http://dx.doi.org/10.1002/cphc.201701104" target="_blank" >http://dx.doi.org/10.1002/cphc.201701104</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/cphc.201701104" target="_blank" >10.1002/cphc.201701104</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10403 - Physical chemistry

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

ChemPhysChem

ISSN

1439-4235

e-ISSN

—

Svazek periodika

19

Číslo periodika v rámci svazku

7

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

7

Strana od-do

873-879

Kód UT WoS článku

000429538400010

EID výsledku v databázi Scopus

2-s2.0-85042127714