title: Protein flexibility in virtual screening: the BACE-1 case study.
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.
authors.affiliation: Dipartimento Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy.
authors.forename: Sandro
authors.initials: S
authors.lastname: Cosconati
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Francesco Saverio
authors.initials: FS
authors.lastname: Di Leva
authors.forename: Valeria
authors.initials: V
authors.lastname: La Pietra
authors.forename: Angela
authors.initials: A
authors.lastname: De Simone
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.forename: Vincenza
authors.initials: V
authors.lastname: Andrisano
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: David S
authors.initials: DS
authors.lastname: Goodsell
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
mesh_terms: D000465:Algorithms; D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D000978:Antiparkinson Agents / Q000737:chemistry*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D062126:Databases, Chemical; D055808:Drug Discovery; D031541:Fluorescence Resonance Energy Transfer; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D013816:Thermodynamics; D014584:User-Computer Interface
chemical_list: D000978:Antiparkinson Agents; D008024:Ligands; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human