Protein Flexibility in Virtual Screening: The BACE‑1 Case Study

• Published in: Journal of chemical information and modeling 2012-10, Vol.52 (10), p.2697-2704
• Main Authors: Cosconati, Sandro, Marinelli, Luciana, Di Leva, Francesco Saverio, La Pietra, Valeria, De Simone, Angela, Mancini, Francesca, Andrisano, Vincenza, Novellino, Ettore, Goodsell, David S, Olson, Arthur J
• Format: Article
• Language: English
• Subjects: Algorithms; Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - chemistry; Analytical chemistry; Antiparkinson Agents - chemistry; Applied sciences; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - chemistry; Binding Sites; Biological and medical sciences; Chemistry; Computer science; control theory; systems; Crystallography, X-Ray; Data processing. List processing. Character string processing; Databases, Chemical; Drug Discovery; Exact sciences and technology; Fluorescence Resonance Energy Transfer; General and physical chemistry; General pharmacology; General. Nomenclature, chemical documentation, computer chemistry; High-Throughput Screening Assays; Humans; Ligands; Medical sciences; Memory organisation. Data processing; Molecular Docking Simulation; Molecular structure; Molecules; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Protein Binding; Protein Conformation; Proteins; Simulation; Software; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry; Thermodynamics; Tumors; User-Computer Interface
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci300390h

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.