LIGSIFT: An open-source tool for ligand structural alignment and virtual screening

Abstract

Motivation: Shape-based alignment of small molecules is a widely used approach in computer-aided drug discovery. Most shapebased ligand structure alignment applications, both commercial and freely available ones, use the Tanimoto coefficient or similar functions for evaluating molecular similarity. Major drawbacks of using such functions are the size dependence of the score and the fact that the statistical significance of the molecular match using such metrics is not reported. Results: We describe a new open-source ligand structure alignment and virtual screening (VS) algorithm, LIGSIFT, that uses Gaussian molecular shape overlay for fast small molecule alignment and a sizeindependent scoring function for efficient VS based on the statistical significance of the score. LIGSIFT was tested against the compounds for 40 protein targets available in the Directory of Useful Decoys and the performance was evaluated using the area under the ROC curve (AUC), the Enrichment Factor (EF) and Hit Rate (HR). LIGSIFT-based VS shows an average AUC of 0.79, average EF values of 20.8 and a HR of 59% in the top 1% of the screened library.