title: Improving Screening Efficiency through Iterative Screening Using Docking and Conformal Prediction.
abstract: 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.
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Fredrik
authors.identifier: 0000-0002-5556-8133
authors.initials: F
authors.lastname: Svensson
authors.affiliation: Swetox, Karolinska Institutet, Unit of Toxicology Sciences , Forskargatan 20, SE-151 36 Södertälje, Sweden.|Department of Computer and Systems Sciences, Stockholm University , Box 7003, SE-164 07 Kista, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Norinder
authors.affiliation: Centre for Molecular Informatics, Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge CB2 1EW, United Kingdom.
authors.forename: Andreas
authors.identifier: 0000-0002-6683-7546
authors.initials: A
authors.lastname: Bender
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays; D062105:Molecular Docking Simulation; D011487:Protein Conformation