Original scientific paper

https://doi.org/10.5562/cca2993

Scaffold Hopping and Bioisosteric Replacements Based on Binding Site Alignments

Samo Lešnik ; Department of Molecular Modeling, National Institute of Chemistry, Hajdrihova 19, SI-1000, Ljubljana, Slovenia
Janez Konc ; Department of Molecular Modeling, National Institute of Chemistry, Hajdrihova 19, SI-1000, Ljubljana, Slovenia
Dušanka Janežič orcid.org/0000-0003-4067-0116 ; Faculty of Mathematics, Natural Sciences and Information Technologies, University of Primorska, Glagoljaška 8, SI-6000, Koper, Slovenia

Abstract

Bioisosteric replacements and scaffold hopping play an important role in modern drug discovery and design, as they enable the change of either a core scaffold or substitutes in a drug structure, thereby facilitating optimization of pharmacokinetic properties and patenting, while the drug retains its activity. A new knowledge-based method was developed to obtain bioisosteric or scaffold replacements based on the extensive data existing in the Protein Data Bank. The method uses all-against-all ProBiS-based protein superimposition to identify ligand fragments that overlap in similar binding sites and could therefore be considered as bioisosteric replacements. The method was demonstrated on a specific example of drug candidate – a nanomolar butyrylcholinesterase inhibitor, on which bioisosteric replacements of the three ring fragments were performed. The new molecule containing bioisosteric replacements was evaluated virtually using AutoDock Vina; a similar score for the original and the compound with replacements was obtained, suggesting that the newly designed bioisostere compound might retain the potency of the original inhibitor.

This work is licensed under a Creative Commons Attribution 4.0 International License.

Keywords

bioisosteres; scaffold hopping; protein alignment; ProBiS; drug design

Hrčak ID:

171908

URI

https://hrcak.srce.hr/171908

Publication date:

19.12.2016.

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