University of Hertfordshire

By the same authors

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Original languageEnglish
Number of pages12
JournalChemical Biology & Drug Design
DOIs
Publication statusPublished - 15 Jul 2022

Abstract

Currently, increasing availability and popularity of designer benzodiazepines (DBZDs) constitutes a primary threat to public health. To assess this threat, the biological activity/potency of DBZDs was investigated using in silico stud-ies. Specific Quantitative Structure Activity Relationship (QSAR) models were developed in Forge™ for the prediction of biological activity (IC50) on the γ- aminobutyric acid A receptor (GABA- AR) of previously identified classified and unclassified DBDZs. A set of new potential ligands resulting from scaffold hop-ping studies conducted with MOE® was also evaluated. Two generated QSAR models (i.e. 3D- field QSAR and RVM) returned very good performance statistics (r2= 0.98 [both] and q2= 0.75 and 0.72, respectively). The DBZDs predicted to be the most active were flubrotizolam, clonazolam, pynazolam and flucotizolam, consistently with what reported in literature and/or drug discussion fora. The scaffold hopping studies strongly suggest that replacement of the pendant phenyl moiety with a five- membered ring could increase biological activity and highlight the existence of a still unexplored chemical space for DBZDs. QSAR could be of use as a preliminary risk assessment model for (newly) identified DBZDs, as well as scaffold hopping for the creation of computational libraries that could be used by regulatory bodies as support tools for scheduling procedures.KEYWORDS3D-QSAR, designer benzodiazepines, Forge™, MedChem, MOE®, recreational drugs, scaffold replacement

Notes

© 2022 John Wiley & Sons Ltd. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1111/cbdd.14119

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