Pose Classification Using Three-Dimensional Atomic Structure-Based Neural Networks Applied to Ion Channel–Ligand Docking

Journal Article · Thu Apr 21 00:00:00 EDT 2022 · Journal of Chemical Information and Modeling

DOI:https://doi.org/10.1021/acs.jcim.1c01510· OSTI ID:1877318

Shim, Heesung ^[1]; Kim, Hyojin ^[2]; Allen, Jonathan E. ^[2]; Wulff, Heike ^[1]

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1. Univ. of California, Davis, CA (United States)
2. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

The identification of promising lead compounds showing pharmacological activities toward a biological target is essential in early stage drug discovery. With the recent increase in available small-molecule databases, virtual high-throughput screening using physics-based molecular docking has emerged as an essential tool in assisting fast and cost-efficient lead discovery and optimization. However, the best scored docking poses are often suboptimal, resulting in incorrect screening and chemical property calculation. We address the pose classification problem by leveraging data-driven machine learning approaches to identify correct docking poses from AutoDock Vina and Glide screens. To enable effective classification of docking poses, we present two convolutional neural network approaches: a three-dimensional convolutional neural network (3D-CNN) and an attention-based point cloud network (PCN) trained on the PDBbind refined set. We demonstrate the effectiveness of our proposed classifiers on multiple evaluation data sets including the standard PDBbind CASF-2016 benchmark data set and various compound libraries with structurally different protein targets including an ion channel data set extracted from Protein Data Bank (PDB) and an in-house KCa3.1 inhibitor data set. Our experiments show that excluding false positive docking poses using the proposed classifiers improves virtual high-throughput screening to identify novel molecules against each target protein compared to the initial screen based on the docking scores.

• Research Organization: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
• Sponsoring Organization: Defense Threat Reduction Agency (DTRA); National Institutes of Health (NIH); USDOE National Nuclear Security Administration (NNSA)
• Grant/Contract Number: AC52-07NA27344
• OSTI ID: 1877318
• Report Number(s): LLNL-JRNL-833101; 1050966
• Journal Information: Journal of Chemical Information and Modeling, Journal Name: Journal of Chemical Information and Modeling Journal Issue: 10 Vol. 62; ISSN 1549-9596
• Publisher: American Chemical Society
• Country of Publication: United States
• Language: English

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
97 MATHEMATICS AND COMPUTING
Crystal structure
Ions
Ligands
Protein structure
Screening assays