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

Academic Article
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Overview

authors

  • Cosconati, S.
  • Marinelli, L.
  • Di Leva, F. S.
  • La Pietra, V.
  • De Simone, A.
  • Mancini, F.
  • Andrisano, V.
  • Novellino, E.
  • Goodsell, David
  • Olson, Arthur

publication date

  • October 2012

journal

  • Journal of Chemical Information and Modeling  Journal

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 ?-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.
  • 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.

subject areas

  • Algorithms
  • Alzheimer Disease
  • Amyloid Precursor Protein Secretases
  • Antiparkinson Agents
  • Aspartic Acid Endopeptidases
  • Binding Sites
  • Crystallography, X-Ray
  • Databases, Chemical
  • Drug Discovery
  • Fluorescence Resonance Energy Transfer
  • High-Throughput Screening Assays
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Conformation
  • Thermodynamics
  • User-Computer Interface
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Identity

PubMed Central ID

  • PMC3523752

International Standard Serial Number (ISSN)

  • 1549-9596

Digital Object Identifier (DOI)

  • 10.1021/ci300390h

PubMed ID

  • 23005250
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Additional Document Info

start page

  • 2697

end page

  • 2704

volume

  • 52

issue

  • 10

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