Investigating combinatorial approaches in virtual screening on human inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3): a case study for small molecule kinases.

Efforts toward improving the predictiveness in tier-based approaches to virtual screening (VS) have mainly focused on protein kinases. Despite their significance as drug targets, small molecule kinases have been rarely tested with these approaches. In this paper, we investigate the efficacy of a pharmacophore screening-combined structure-based docking approach on the human inducible 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase, an emerging target for cancer chemotherapy. Six out of a total 1364 compounds from NCI's Diversity Set II were selected as true actives via throughput screening. Using a database constructed from these compounds, five programs were tested for structure-based docking (SBD) performance, the MOE of which showed the highest enrichments and second highest screening rates. Separately, using the same database, pharmacophore screening was performed, reducing 1364 compounds to 287 with no loss in true actives, yielding an enrichment of 4.75. When SBD was retested with the pharmacophore filtered database, 4 of the 5 SBD programs showed significant improvements to enrichment rates at only 2.5% of the database, with a 7-fold decrease in an average VS time. Our results altogether suggest that combinatorial approaches of VS technologies are easily applicable to small molecule kinases and, moreover, that such methods can decrease the variability associated with single-method SBD approaches.