SCORCH: Improving structure-based virtual screening with machine learning classifiers, data augmentation, and uncertainty estimation

Miles McGibbon, Sam Money-Kyrle, Vincent Blay, Douglas R. Houston

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Introduction
The discovery of a new drug is a costly and lengthy endeavour. The computational prediction of which small molecules can bind to a protein target can accelerate this process if the predictions are fast and accurate enough. Recent machine-learning scoring functions re-evaluate the output of molecular docking to achieve more accurate predictions. However, previous scoring functions were trained on crystalised protein-ligand complexes and datasets of decoys. The limited availability of crystal structures and biases in the decoy datasets can lower the performance of scoring functions.

Objectives
To address key limitations of previous scoring functions and thus improve the predictive performance of structure-based virtual screening.

Methods
A novel machine-learning scoring function was created, named SCORCH (Scoring COnsensus for RMSD-based Classification of Hits). To develop SCORCH, training data is augmented by considering multiple ligand poses and stratifying pose classification by RMSD from the native pose. Decoy bias is addressed by generating property-matched decoys for each ligand and using the same methodology for preparing and docking decoys and ligands. A consensus of 3 different machine learning approaches is also used to improve performance.

Results
We find that multi-pose augmentation improves the docking power and screening power of machine-learning scoring functions on independent benchmark datasets. SCORCH outperforms an equivalent scoring function trained on single poses, with a 1% enrichment factor (EF) of 13.78 vs. 10.86 on 18 DEKOIS 2.0 targets and a mean native pose rank of 5.9 vs 30.4 on CSAR 2014. Additionally, SCORCH outperforms widely used scoring functions in virtual screening and pose prediction on independent benchmark datasets.

Conclusion
By rationally addressing key limitations of previous scoring functions, SCORCH improves the performance of virtual screening. SCORCH also provides an estimate of its uncertainty, which can help reduce the cost and time required for drug discovery.
Original languageEnglish
JournalJournal of Advanced Research
Early online date25 Jul 2022
DOIs
Publication statusE-pub ahead of print - 25 Jul 2022

Keywords / Materials (for Non-textual outputs)

  • docking
  • scoring
  • virtual screening
  • machine learning
  • drug discovery
  • neural networks

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