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.

DOCK 6: Impact of new features and current docking performance

“…Ongoing work in our laboratory, as well as other groups, includes evaluating methods to effectively model receptor conformational variability or ensembles during docking. [34,131–135] Under ideal docking conditions, success should be independent of the actual starting receptor structure. In practice, however, the starting conditions (including different forms, mutations, variable induced fit effects, etc.)…”

Advances in the identification of β-secretase inhibitors

“…As stated previously, the high cost and low chemical space coverage of chemical libraries is often pointed out. Although in silico screening has been commonly applied to drug discovery research and some case studies were reported using well-known BACE1 inhibitors [146], successful cases of BACE1 inhibitor identification by the in silico HTS strategy are rarely reported. The reason is described in Section 9.…”

DARC: Mapping Surface Topography by Ray-Casting for Effective Virtual Screening at Protein Interaction Sites

“…A variety of methods exist for incorporating receptor flexibility, typically by docking against multiple receptor conformations from either crystal structures [38–42] or simulation [43–45]. …”

“…Variation in the protein structure is most commonly included in virtual screening by first generating an ensemble of relevant conformations from crystal structures [38–42] or simulation [43–45], and then separately screening against each of these conformations. Nonetheless, identifying the optimal conformations to include in these ensembles is still a challenging task [111–113].…”