RAPID-Net: Accurate Pocket Identification for Binding-Site-Agnostic Docking

TL;DR

RAPID-Net is a deep learning tool that accurately predicts druggable pockets on proteins, enhancing docking accuracy and enabling large-scale virtual screening for drug discovery, including identification of allosteric sites.

Contribution

This work introduces RAPID-Net, a novel deep learning-based pocket predictor that outperforms existing tools in accuracy and scalability, and demonstrates its utility in drug discovery pipelines.

Findings

RAPID-Net-guided docking achieves over 54% Top-1 accuracy with RMSD < 2 Å.

RAPID-Net outperforms PUResNet and Kalasanty in benchmark tests.

It uncovers additional binding pockets on SARS-CoV-2 RNA polymerase, including secondary cavities.

Abstract

Accurate identification of druggable pockets and their features is essential for structure-based drug design and effective downstream docking. Here, we present RAPID-Net, a deep learning-based algorithm designed for the accurate prediction of binding pockets and seamless integration with docking pipelines. On the PoseBusters benchmark, RAPID-Net-guided AutoDock Vina achieves 54.9% of Top-1 poses with RMSD < 2 A and satisfying the PoseBusters chemical-validity criterion, compared to 49.1% for DiffBindFR. On the most challenging time split of PoseBusters aiming to assess generalization ability (structures submitted after September 30, 2021), RAPID-Net-guided AutoDock Vina achieves 53.1% of Top-1 poses with RMSD < 2 A and PB-valid, versus 59.5% for AlphaFold 3. Notably, in 92.2% of cases, RAPID-Net-guided Vina samples at least one pose with RMSD < 2 A (regardless of its rank), indicating that pose ranking, rather than sampling, is the primary accuracy bottleneck. The lightweight inference, scalability, and competitive accuracy of RAPID-Net position it as a viable option for large-scale virtual screening campaigns. Across diverse benchmark datasets, RAPID-Net outperforms other pocket prediction tools, including PUResNet and Kalasanty, in both docking accuracy and pocket-ligand intersection rates. Furthermore, we demonstrate the potential of RAPID-Net to accelerate the development of novel therapeutics by highlighting its performance on pharmacologically relevant targets. RAPID-Net accurately identifies distal functional sites, offering new opportunities for allosteric inhibitor design. In the case of the RNA-dependent RNA polymerase of SARS-CoV-2, RAPID-Net uncovers a wider array of potential binding pockets than existing predictors, which typically annotate only the orthosteric pocket and overlook secondary cavities.