Data driven selection of consensus docking pipelines for structure based hit identification

Abstract

Structure-based virtual screening (SBVS) is a cornerstone of computer-aided drug design, yet its success depends on selecting a combination of docking tools, scoring function (SF), and ranking strategies. MolDockLab addresses this challenge with an automated, data-driven framework that optimizes SBVS workflows for a protein target, balancing predictive performance and computational efficiency. It systematically explores combinations of five docking engines, 15 SF, and three consensus ranking strategies using a calibration set of ≈ 200 compounds with known bioactivity, and applies the best-correlating workflow to the larger screening library. Final hit selection from the top 1% integrates protein-ligand interaction profiler (PLIP)-derived interaction fingerprints, structural-diversity assessment, and expert visual inspection. In a retrospective evaluation on the epidermal growth factor receptor (EGFR), the chosen pipeline achieved a Spearman correlation of 0.36 and an enrichment factor (EF) at 10% of 1.57, consistent with calibration. Prospectively, for the energy coupling factor transporters (ECF-T)-a challenging transmembrane target with a cryptic binding site and no co-crystallized ligand-the pipeline reached a correlation of 0.45 and enrichment of 3.13. Post-processing enabled in vitro confirmation of two chemically novel inhibitors rivaling the most potent ECF-T inhibitors reported to date.