Deep Learning with Geometry-Enhanced Molecular Representation for Augmentation of Large-Scale Docking-Based Virtual Screening

Structure-based virtual screening has been a crucial tool in drug discovery for decades. However, as the chemical space expands, the existing structure-based virtual screening techniques based on molecular docking and scoring struggle to handle billion-entry ultralarge libraries due to the high computational cost. To address this challenge, people have resorted to machine learning techniques to enhance structure-based virtual screening for efficiently exploring the vast chemical space. In those cases, compounds are usually treated as sequential strings or two-dimensional topology graphs, limiting their ability to incorporate three-dimensional structural information for downstream tasks. We herein propose a novel deep learning protocol, GEM-Screen, which utilizes the geometry-enhanced molecular representation of the compounds docking to a specific target and is trained on docking scores of a small fraction of a library through an active learning strategy to approximate the docking outcome for yet nontraining entries. This protocol is applied to virtual screening campaigns against the AmpC and D4 targets, demonstrating that GEM-Screen enriches more than 90% of the hit scaffolds for AmpC in the top 4% of model predictions and more than 80% of the hit scaffolds for D4 in the same top-ranking size of library. GEM-Screen can be used in conjunction with traditional docking programs for docking of only the top-ranked compounds to avoid the exhaustive docking of the whole library, thus allowing for discovering top-scoring compounds from billion-entry libraries in a rapid yet accurate fashion.