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

Abstract

Fruitful 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 1,364 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, of which, MOE showed the highest enrichments and second highest screening rates. Separately, using the same database, pharmacophore screening was performed, reducing 1,364 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.

Flavin nucleotides act as electron shuttles mediating reduction of the [2Fe-2S] clusters in mitochondrial outer membrane protein mitoNEET

“…Our protocol for AutoDockVina-based Virtual Screening [37] is a modification from Garret M. Morris’ (The Scripps Research Institute, La Jolla, CA) [36]. The best docking models for the FMN binding in mitoNEET are shown in Figure 6A.…”

“…The validity of this protocol was established during other studies [37]. Partial conformational flexibility was allowed to the residues in direct contacts with targets.…”

Computational Screening of Molecules Approved in Phase-I Clinical Trials to Identify 3CL Protease Inhibitors to Treat COVID-19

“…In the case of COVID19 where it is crucial to find safe and therapeutic drugs very quickly, computational screening of drug libraries could identify drug candidates for immediate clinical testing. Indeed, virtual screening (VS) of chemically available ligand databases has become an important tool with which to explore chemical space [2,3] [4,5] and to accelerate the initial stages of drug discovery. The aim is to rapidly identify potential hit molecules which can then be evaluated experimentally and clinically.…”