Protein flexibility in virtual screening: The BACE-1 case study

Sandro Cosconati, Luciana Marinelli, Francesco Saverio Di Leva, Valeria La Pietra, Angela De Simone, Francesca Mancini, Vincenza Andrisano, Ettore Novellino, David S. Goodsell, Arthur J. Olson

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Abstract

Simulating protein flexibility is a major issue in the docking-based drug-design process for which a single methodological solution does not exist. In our search of new anti-Alzheimer ligands, we were faced with the challenge of including receptor plasticity in a virtual screening campaign aimed at finding new β-secretase inhibitors. To this aim, we incorporated protein flexibility in our simulations by using an ensemble of static X-ray enzyme structures to screen the National Cancer Institute database. A unified description of the protein motion was also generated by computing and combining a set of grid maps using an energy weighting scheme. Such a description was used in an energy-weighted virtual screening experiment on the same molecular database. Assessment of the enrichment factors from these two virtual screening approaches demonstrated comparable predictive powers, with the energy-weighted method being faster than the ensemble method. The in vitro evaluation demonstrated that out of the 32 tested ligands, 17 featured the predicted enzyme inhibiting property. Such an impressive success rate (53.1%) demonstrates the enhanced power of the two methodologies and suggests that energy-weighted virtual screening is a more than valid alternative to ensemble virtual screening given its reduced computational demands and comparable performance.

Original languageEnglish (US)
Pages (from-to)2697-2704
Number of pages8
JournalJournal of Chemical Information and Modeling
Volume52
Issue number10
DOIs
StatePublished - Oct 22 2012

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Cosconati, S., Marinelli, L., Di Leva, F. S., La Pietra, V., De Simone, A., Mancini, F., Andrisano, V., Novellino, E., Goodsell, D. S., & Olson, A. J. (2012). Protein flexibility in virtual screening: The BACE-1 case study. Journal of Chemical Information and Modeling, 52(10), 2697-2704. https://doi.org/10.1021/ci300390h