General Purpose Structure-Based Drug Discovery Neural Network Score Functions with Human-Interpretable Pharmacophore Maps

J Chem Inf Model. 2021 Feb 22;61(2):603-620. doi: 10.1021/acs.jcim.0c01001. Epub 2021 Jan 26.

Abstract

The BioChemical Library (BCL) is an academic open-source cheminformatics toolkit comprising ligand-based virtual high-throughput screening (vHTS) tools such as quantitative structure-activity/property relationship (QSAR/QSPR) modeling, small molecule flexible alignment, small molecule conformer generation, and more. Here, we expand the capabilities of the BCL to include structure-based virtual screening. We introduce two new score functions, BCL-AffinityNet and BCL-DockANNScore, based on novel distance-dependent signed protein-ligand atomic property correlations. Both metrics are conventional feed-forward dropout neural networks trained on the new descriptors. We demonstrate that BCL-AffinityNet is one of the top performing score functions on the comparative assessment of score functions 2016 affinity prediction and affinity ranking tasks. We also demonstrate that BCL-AffinityNet performs well on the CSAR-NRC HiQ I and II test sets. Furthermore, we demonstrate that BCL-DockANNScore is competitive with multiple state-of-the-art methods on the docking power and screening power tasks. Finally, we show how our models can be decomposed into human-interpretable pharmacophore maps to aid in hit/lead optimization. Altogether, our results expand the utility of the BCL for structure-based scoring to aid small molecule discovery and design. BCL-AffinityNet, BCL-DockANNScore, and the pharmacophore mapping application, as well as the remainder of the BCL cheminformatics toolkit, are freely available with an academic license at the BCL Commons site hosted on http://meilerlab.org/.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Cheminformatics
  • Drug Discovery*
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Neural Networks, Computer
  • Quantitative Structure-Activity Relationship*

Substances

  • Ligands