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Computational methods for scaffold hopping

Schuffenhauer, Ansgar (2012) Computational methods for scaffold hopping. Wiley Interdisciplinary Reviews: Computational Molecular Sciences, 2 (6). pp. 842-867. ISSN 1759-0884


It is not uncommon in drug discovery that the core fragment, typically called scaffold, of a molecule with an interesting biological activity cannot be developed further because of issues related to intellectual property, physico-chemical properties, metabolic stability or toxicity, to name only a few reasons. In this situation it is desirable to replace this scaffold with another scaffold having a different chemical connectivity, but the similar geometric properties and pharmacophore features. Such a replacement is called scaffold hopping. There now several computational tools available to supporting the identification of ligands with a different scaffold starting from know ligands, and if available their bound conformation. A broad variety of ligand based virtual screening and scoring methods capable of scaffold hopping is available comprising besides pharmacophore searches field and shape based similarity, alignment free similarity measures over both 3D and connectivity based descriptors and fragment based methods. While within the last decade for many of them a successful prospective use has been reported, a rigorous systematic benchmarking of scaffold-hopping methods is still extremely challenging, especially due to the lacking consensus in the definition of a scaffold. Computational scaffold extraction methods are available however, and been used as an approximate benchmark for scaffold hopping, despite several drawbacks. While in many systematic retrospective studies connectivity based methods were shown to be at least equally effective as 3D methods, especially when the conformations of the reference structures were generated with a conformer generator. In prospective comparison studies, where a hypothesis of the 3D binding conformation was available and used, often 3D methods were found to give superior results

Item Type: Article
Keywords: scaffold hopping, ligand based virtual screening
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14