Systematic comparison of the performance of different 2D and 3D ligand-based virtual screening methodologies to discover anticonvulsant drugs

MAURICIO E. DI IANNI; MELISA GANTNER; MARÍA E. RUIZ; EDUARDO A. CASTRO; LUIS E. BRUNO BLANCH; ALAN TALEVI

COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING

BENTHAM SCIENCE PUBL LTD

Lugar: Oak Park; Año: 2015 vol. 18 p. 387 - 398

1386-2073

Virtual screening encompasses a wide range of computational approaches aimed at the high-throughput, cost-efficient exploration of chemical libraries or databases to discover new bioactive compounds or novel medical indications of known drugs. Here, we have performed a systematic comparison of the performance of a large number of 2D and 3D ligand-based approaches (2D and 3D similarity, QSAR models, pharmacophoric hypothesis) in a simulated virtual campaign on a chemical library containing 50 known anticonvulsant drugs and 950 decoys with no previously reported of anticonvulsant effect. To perform such comparison we resorted to Receiver Operating Characteristic curves. We also tested the relative performance of consensus methodologies. Our results indicate that the selective combination of the individual approaches (through voting and ranking combination schemes) significantly outperforms the individual algorithms and/or models. Among the best-performing individual approaches, 2D similarity search based on circular fingerprints and 3D similarity approaches should be highlighted. Combining the results from different query molecules also led to enhanced enrichment.