Incorporating virtual reactions into a logic-based ligand-based virtual screening method to discover new leads
Author(s)
Reynolds, CR
Muggleton, SH
Sternberg, MJE
Type
Journal Article
Abstract
The use of virtual screening has become increasingly central to the drug development pipeline, with ligand-based virtual screening used to screen databases of compounds to predict their bioactivity against a target. These databases can only represent a small fraction of chemical space, and this paper describes a method of exploring synthetic space by applying virtual reactions to promising compounds within a database, and generating focussed libraries of predicted derivatives. A ligand-based virtual screening tool Investigational Novel Drug Discovery by Example (INDDEx) is used as the basis for a system of virtual reactions. The use of virtual reactions is estimated to open up a potential space of 1.21×1012 potential molecules. A de novo design algorithm known as Partial Logical-Rule Reactant Selection (PLoRRS) is introduced and incorporated into the INDDEx methodology. PLoRRS uses logical rules from the INDDEx model to select reactants for the de novo generation of potentially active products. The PLoRRS method is found to increase significantly the likelihood of retrieving molecules similar to known actives with a p-value of 0.016. Case studies demonstrate that the virtual reactions produce molecules highly similar to known actives, including known blockbuster drugs.
Date Issued
2015-03-20
Date Acceptance
2015-01-08
Citation
Molecular Informatics, 2015, 34 (9), pp.615-625
ISSN
1868-1751
Publisher
Wiley-VCH Verlag
Start Page
615
End Page
625
Journal / Book Title
Molecular Informatics
Volume
34
Issue
9
Copyright Statement
© 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Subjects
Science & Technology
Life Sciences & Biomedicine
Technology
Chemistry, Medicinal
Computer Science, Interdisciplinary Applications
Mathematical & Computational Biology
Pharmacology & Pharmacy
Computer Science
Virtual screening
Reactions
Ligand
Synthesis
Machine learning
DRUG DISCOVERY
CHEMISTRY
DOCKING
DESIGN
ROSIGLITAZONE
TECHNOLOGY
MOLECULES
LIBRARIES
DATABASE
SMILES
0304 Medicinal And Biomolecular Chemistry
0307 Theoretical And Computational Chemistry
0601 Biochemistry And Cell Biology
Publication Status
Published