Optimization and validation of a docking-scoring protocol; application to virtual screening for COX-2 inhibitors.
To exploit available structural information about the cyclooxygenase enzyme for the virtual screening of large chemical libraries, a docking-scoring protocol was tuned and validated. The screening accuracy was assessed using a series of known inhibitors and a set of diverse a priori inactive compounds that was seeded with known active ligands. The major parameters of the DOCK algorithm were investigated. A large improvement of the results was obtained on tweaking some of them. The generated complexes were rescored using six scoring functions. In this way, the striking importance of this step was demonstrated, as well as the good performances of DOCK energy and SCORE for this target. The results were further improved via a consensus approach. As a first application, a subset of a large compound library was screened using this protocol. Among the compounds that were selected for biological testing, a third of them turned out to have a significant enzyme inhibition.
Mozziconacci
Jean-Christophe
JC
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d'Orléans, BP 6759, F-45067 Orléans Cedex 2, France.
Arnoult
Eric
E
Bernard
Philippe
P
Do
Quoc Tuan
QT
Marot
Christophe
C
Morin-Allory
Luc
L
D018360:Crystallography, X-Ray; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D016208:Databases, Factual; D006801:Humans; D007124:Immunoenzyme Techniques; D008565:Membrane Proteins; D008968:Molecular Conformation; D015394:Molecular Structure; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry* / Q000378:metabolism*; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D013449:Sulfonamides; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases