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Improving Screening Efficiency through Iterative Screening Using Docking and Conformal Prediction

Svensson, Fredrik ; Norinder, Ulf ; Bender, Andreas

Journal of chemical information and modeling, 2017-03-27, Vol.57 (3), p.439-444 [Peer Reviewed Journal]

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  • Title:
    Improving Screening Efficiency through Iterative Screening Using Docking and Conformal Prediction
  • Author: Svensson, Fredrik ; Norinder, Ulf ; Bender, Andreas
  • Subjects: Drug Evaluation, Preclinical - methods ; Protein Conformation ; Molecular Docking Simulation ; High-Throughput Screening Assays ; Medicin och hälsovetenskap
  • Is Part Of: Journal of chemical information and modeling, 2017-03-27, Vol.57 (3), p.439-444
  • Description: High-throughput screening, where thousands of molecules rapidly can be assessed for activity against a protein, has been the dominating approach in drug discovery for many years. However, these methods are costly and require much time and effort. In order to suggest an improvement to this situation, in this study, we apply an iterative screening process, where an initial set of compounds are selected for screening based on molecular docking. The outcome of the initial screen is then used to classify the remaining compounds through a conformal predictor. The approach was retrospectively validated using 41 targets from the Directory of Useful Decoys, Enhanced (DUD-E), ensuring scaffold diversity among the active compounds. The results show that 57% of the remaining active compounds could be identified while only screening 9.4% of the database. The overall hit rate (7.6%) was also higher than when using docking alone (5.2%). When limiting the search to the top scored compounds from docking, 39.6% of the active compounds could be identified, compared to 13.5% when screening the same number of compounds solely based on docking. The use of conformal predictors also gives a clear indication of the number of compounds to screen in the next iteration. These results indicate that iterative screening based on molecular docking and conformal prediction can be an efficient way to find active compounds while screening only a small part of the compound collection.
  • Publisher: United States: American Chemical Society
  • Language: English
  • Identifier: ISSN: 1549-9596
    ISSN: 1549-960X
    EISSN: 1549-960X
    DOI: 10.1021/acs.jcim.6b00532
    PMID: 28195474
  • Source: DataCite

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