10.1021/ci600298r.s001
Alexander Weber
Alexander
Weber
Markus Böhm
Markus
Böhm
Claudiu T. Supuran
Claudiu T.
Supuran
Andrea Scozzafava
Andrea
Scozzafava
Christoph A. Sotriffer
Christoph A.
Sotriffer
Gerhard Klebe
Gerhard
Klebe
3D QSAR Selectivity Analyses of Carbonic Anhydrase Inhibitors: Insights for the
Design of Isozyme Selective Inhibitors
American Chemical Society
2006
InhibitorsA 3 D QSAR selectivity analysis
87 CA inhibitors
CA isozymes
3 D QSAR Selectivity Analyses
novel CA inhibitors
3 D QSAR selectivity models
CA inhibitors
Correct binding modes
3 D QSAR models
docking program AUTODOCK
CA IV isoforms
CoMSIA 3 D QSAR models
II
2006-11-27 00:00:00
Journal contribution
https://acs.figshare.com/articles/journal_contribution/3D_QSAR_Selectivity_Analyses_of_Carbonic_Anhydrase_Inhibitors_Insights_for_the_Design_of_Isozyme_Selective_Inhibitors/3045178
A 3D QSAR selectivity analysis of carbonic anhydrase (CA) inhibitors using a data set of 87 CA inhibitors
is reported. After ligand minimization in the binding pockets of CA I, CA II, and CA IV isoforms, selectivity
CoMFA and CoMSIA 3D QSAR models have been derived by taking the affinity differences (Δp<i>K</i><sub>i</sub>) with
respect to two CA isozymes as independent variables. Evaluation of the developed 3D QSAR selectivity
models allows us to determine amino acids in the respective CA isozymes that possibly play a crucial role
for selective inhibition of these isozymes. We further combined the ligand-based 3D QSAR models with
the docking program AUTODOCK in order to screen for novel CA inhibitors. Correct binding modes are
predicted for various CA inhibitors with respect to known crystal structures. Furthermore, in combination
with the developed 3D QSAR models we could successfully estimate the affinity of CA inhibitors even in
cases where the applied scoring function failed. This novel strategy to combine AUTODOCK poses with
CoMFA/CoMSIA 3D QSAR models can be used as a guideline to assess the relevance of generated binding
modes and to accurately predict the binding affinity of newly designed CA inhibitors that could play a
crucial role in the treatment of pathologies such as tumors, obesity, or glaucoma.