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

Abstract

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.

D3R grand challenge 4: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

“…Our experience shows that multiple docking/cheminformatics software tools produced submissions of comparable accuracy. These software packages include docking software such as Glide [62,63], ICM [64], Corina [65], Gold [66], Cactvs[67], Rosetta [68], and EFindSite [69], and ligand preparation software such as Brikard [70]. In addition, almost all submissions in Table 1 used more than one type of software package in their workflow, preferring rather to combine multiple docking software packages.…”

Local Alignment of Ligand Binding Sites in Proteins for Polypharmacology and Drug Repositioning

“…e FindSite is a ligand binding site prediction and virtual screening algorithm that detects common ligand binding sites in a set of evolutionarily related proteins identified by meta-threading [14, 15]. In order to perform binding site annotation with e FindSite, users can employ either its standalone version or webserver located at http://www.brylinski.org/efindsite (see Note 2).…”

“…Note that bound ThTDP ligands are shown in Fig. 3 only to assess the accuracy of binding pocket prediction with e FindSite, which detects and annotates binding sites in ligand-free protein structures [14, 15]. …”

Human Rab8b Protein as a Cancer Target - An In Silico Study

“…Active site (binding pockets) is the region of the protein that is responsible for its activity [29,30]. The active site of Rab8bprotein is predicted using Sitemap of Schrodinger suite, CASTp and efindsite servers [31][32][33][34]. The Grid generated around the active site region, of size 80 × 80 × 80 Å 3 , is used for further virtual screening studies [35].…”