Structure-based virtual screening: an application to human topoisomerase II alpha.
The eukaryotic topoisomerase II is involved in several vital processes, such as replication, transcription, and recombination. Many compounds interfering with the catalytic action of this enzyme are efficient in human cancer chemotherapy. We applied a methodology combining molecular modeling and virtual screening techniques to identify human topoisomerase II alphainhibitors. Data from structural biology and enzymatic assays together with a good background on the enzyme mechanism of action were helpful in the approach. A human topoisomerase II alpha model provided an insight into the structural features responsible for the activity of the enzyme. A protocol comprising several substructural and protein structure-based three-dimensional pharmacophore filters enabled the successful retrieving of inhibitors of the enzyme from large databases of compounds, thus validating the approach. A subset of protein structural features required for the enzyme inhibition at the protein-DNA interface were identified and incorporated into the pharmacophore models. Compounds sharing a DNA-intercalating chromophore and a moiety interfering with the protein active site emerged as good inhibitors.
Christmann-Franck
Serge
S
Département de Biologie et Pharmacologie Structurales, UMR 8113 CNRS, LBPA, ENS Cachan, 61 avenue du Président Wilson, 94235 Cachan Cedex, France.
Bertrand
Hugues-Olivier
HO
Goupil-Lamy
Anne
A
der Garabedian
P Arsène
PA
Mauffret
Olivier
O
Hoffmann
Rémy
R
Fermandjian
Serge
S
D000595:Amino Acid Sequence; D000951:Antigens, Neoplasm; D001665:Binding Sites; D004250:DNA Topoisomerases, Type II / Q000737:chemistry; D004268:DNA-Binding Proteins; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D016415:Sequence Alignment; D013698:Templates, Genetic; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II