e FindSite: Enhanced Fingerprint‐Based Virtual Screening Against Predicted Ligand Binding Sites in Protein Models

A standard practice for lead identification in drug discovery is ligand virtual screening, which utilizes computing technologies to detect small compounds that likely bind to target proteins prior to experimental screens. A high accuracy is often achieved when the target protein has a resolved crystal structure; however, using protein models still renders significant challenges. Towards this goal, we recently developed eFindSite that predicts ligand binding sites using a collection of effective algorithms, including meta-threading, machine learning and reliable confidence estimation systems. Here, we incorporate fingerprint-based virtual screening capabilities in eFindSite in addition to its flagship role as a ligand binding pocket predictor. Virtual screening benchmarks using the enhanced Directory of Useful Decoys demonstrate that eFindSite significantly outperforms AutoDock Vina as assessed by several evaluation metrics. Importantly, this holds true regardless of the quality of target protein structures. As a first genome-wide application of eFindSite, we conduct large-scale virtual screening of the entire proteome of Escherichia coli with encouraging results. In the new approach to fingerprint-based virtual screening using remote protein homology, eFindSite demonstrates its compelling proficiency offering a high ranking accuracy and low susceptibility to target structure deformations. The enhanced version of eFindSite is freely available to the academic community at http://www.brylinski.org/efindsite.