Extraction and visualization of potential pharmacophore points using support vector machines: application to ligand-based virtual screening for COX-2 inhibitors.
Support vector machines (SVM) were trained to predict cyclooxygenase 2 (COX-2) and thrombin inhibitors. The classifiers were obtained using sets of known COX-2 and thrombin inhibitors as "positive examples" and a large collection of screening compounds as "negative examples". Molecules were encoded by topological pharmacophore-point triangles. In retrospective virtual screening, 50-90% of the known active compounds were listed within the first 0.1% of the ranked database. To check the validity of the constructed classifiers, we developed a method for feature extraction and visualization using SVM. As a result, potential pharmacophore points were weighted according to their importance for COX-2 and thrombin inhibition. Known thrombin and COX-2 pharmacophore points were correctly recognized by the machine learning system. In a prospective virtual screening study, several potential COX-2 inhibitors were predicted and tested in a cellular activity assay. A benzimidazole derivative exhibited significant inhibitory activity with an IC(50) of 0.2 microM, which is better than Celecoxib in our assay. It was demonstrated that the SVM machine-learning method can be used in virtual screening and be analyzed in a human-interpretable way that results in a set of rules for designing novel molecules.
Franke
Lutz
L
Institut für Organische Chemie und Chemische Biologie and Institut für Pharmazeutische Chemie, Johann Wolfgang Goethe-Universität, Marie-Curie-Strasse 9, D-60439 Frankfurt, Germany.
Byvatov
Evgeny
E
Werz
Oliver
O
Steinhilber
Dieter
D
Schneider
Petra
P
Schneider
Gisbert
G
D001665:Binding Sites; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000737:chemistry*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000737:chemistry
D052246:Cyclooxygenase 2 Inhibitors; D008024:Ligands; D051546:Cyclooxygenase 2; D013917:Thrombin