DENVIS: scalable and high-throughput virtual screening using graph neural networks with atomic and surface protein pocket features

Abstract

Computational methods for virtual screening can dramatically accelerate early-stage drug discovery by identifying potential hits for a specified target. Docking algorithms traditionally use physics-based simulations to address this challenge by estimating the binding orientation of a query protein-ligand pair and a corresponding binding affinity score. Over the recent years, classical and modern machine learning architectures have shown potential for outperforming traditional docking algorithms. Nevertheless, most learning-based algorithms still rely on the availability of the protein-ligand complex binding pose, typically estimated via docking simulations, which leads to a severe slowdown of the overall virtual screening process. A family of algorithms processing target information at the amino acid sequence level avoid this requirement, however at the cost of processing protein data at a higher representation level. We introduce deep neural virtual screening (DENVIS), an end-to-end pipeline for virtual screening using graph neural networks (GNNs). By performing experiments on two benchmark databases, we show that our method performs competitively to several docking-based, machine learning-based, and hybrid docking/machine learning-based algorithms. By avoiding the intermediate docking step, DENVIS exhibits several orders of magnitude faster screening times (i.e., higher throughput) than both docking-based and hybrid models. When compared to an amino acid sequence-based machine learning model with comparable screening times, DENVIS achieves dramatically better performance. Some key elements of our approach include protein pocket modelling using a combination of atomic and surface features, the use of model ensembles, and data augmentation via artificial negative sampling during model training. In summary, DENVIS achieves competitive to state-of-the-art virtual screening performance, while offering the potential to scale to billions of molecules using minimal computational resources. Graphical TOC Entry O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=94 SRC="FIGDIR/small/484710v3_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@ed723dorg.highwire.dtl.DTLVardef@e72e5aorg.highwire.dtl.DTLVardef@1942fcborg.highwire.dtl.DTLVardef@1cdc58b_HPS_FORMAT_FIGEXP M_FIG C_FIG