Docking and scoring of metallo-beta-lactamases inhibitors
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Docking and scoring of metallo-beta-lactamases inhibitors. / Olsen, Lars; Pettersson, Ingrid; Hemmingsen, Lars; Adolph, Hans-Werner; Jørgensen, Flemming Steen.
In: Journal of Computer - Aided Molecular Design, Vol. 18, No. 4, 2004, p. 287-302.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Docking and scoring of metallo-beta-lactamases inhibitors
AU - Olsen, Lars
AU - Pettersson, Ingrid
AU - Hemmingsen, Lars
AU - Adolph, Hans-Werner
AU - Jørgensen, Flemming Steen
PY - 2004
Y1 - 2004
N2 - The performance of the AutoDock, GOLD and FlexX docking programs was evaluated for docking of dicarboxylic acid inhibitors into metallo-beta-lactamases (MBLs). GOLD provided the best overall performance, with RMSDs between experimental and docked structures of 1.8-2.6 A and a good correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores. GOLD was selected for a test including a broad spectrum of inhibitors for which experimental MBL-inhibitor binding affinities are available. This study revealed that (1) for most compound classes (dicarboxylic acids, tetrazoles, sulfonylhydrazones, and peptide-like compounds) there is a good correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores, (2) the correlation only holds within a given class, that is, scores of compounds from different classes cannot be directly compared, (3) for some compound classes (e.g. small sulphur compounds) there is no direct correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores. Using partial least squares methods, a model with R2 = 0.82 and Q2 = 0.78 for the training set was obtained based on the GOLD score and descriptors associated with binding of the IMP-1 inhibitors to the enzyme. The external Q2 for the test set is 0.73. This final model for prediction of IMP-1 MBL-inhibitor affinity handled all known classes of MBL-inhibitors, except small sulphur compounds.
AB - The performance of the AutoDock, GOLD and FlexX docking programs was evaluated for docking of dicarboxylic acid inhibitors into metallo-beta-lactamases (MBLs). GOLD provided the best overall performance, with RMSDs between experimental and docked structures of 1.8-2.6 A and a good correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores. GOLD was selected for a test including a broad spectrum of inhibitors for which experimental MBL-inhibitor binding affinities are available. This study revealed that (1) for most compound classes (dicarboxylic acids, tetrazoles, sulfonylhydrazones, and peptide-like compounds) there is a good correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores, (2) the correlation only holds within a given class, that is, scores of compounds from different classes cannot be directly compared, (3) for some compound classes (e.g. small sulphur compounds) there is no direct correlation between the experimentally determined MBL-inhibitor affinities and the GOLD scores. Using partial least squares methods, a model with R2 = 0.82 and Q2 = 0.78 for the training set was obtained based on the GOLD score and descriptors associated with binding of the IMP-1 inhibitors to the enzyme. The external Q2 for the test set is 0.73. This final model for prediction of IMP-1 MBL-inhibitor affinity handled all known classes of MBL-inhibitors, except small sulphur compounds.
KW - Computational Biology
KW - Enzyme Inhibitors
KW - Ligands
KW - Models, Molecular
KW - Protein Binding
KW - Software
KW - Succinic Acids
KW - beta-Lactamases
M3 - Journal article
C2 - 15562992
VL - 18
SP - 287
EP - 302
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
SN - 0920-654X
IS - 4
ER -
ID: 38393938