Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan;101(1):40-51.
doi: 10.1111/cbdd.14119. Epub 2022 Sep 5.

In silico studies on recreational drugs: 3D quantitative structure activity relationship prediction of classified and de novo designer benzodiazepines

Valeria Catalani  1 , Giuseppe Floresta  2 , Michelle Botha  1 , John Martin Corkery  1 , Amira Guirguis  1   3 , Alessandro Vento  4 , Vincenzo Abbate  2 , Fabrizio Schifano  1
Affiliations

In silico studies on recreational drugs: 3D quantitative structure activity relationship prediction of classified and de novo designer benzodiazepines

Valeria Catalani et al. Chem Biol Drug Des. 2023 Jan.

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 studies. 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 hopping 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.

Keywords: 3D-QSAR; Forge™; MOE®; MedChem; designer benzodiazepines; recreational drugs; scaffold replacement.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

References

REFERENCES

    1. ACMD. (2020a). Addendum to ACMD's report on novel benzodiazepines. Retrieved January 31, 2022, from https://www.gov.uk/government/publications/novel-benzodiazepines-prevale...
    1. ACMD. (2020b). Novel benzodiazepines a review of the evidence of use and harms of novel benzodiazepines. Retrieved from https://www.gov.uk
    1. Alam, S., & Khan, F. (2017). 3D-QSAR studies on Maslinic acid analogs for anticancer activity against breast cancer cell line MCF-7. Scientific Reports, 7(1), 6019. https://doi.org/10.1038/S41598-017-06131-0
    1. Amundarain, M. J., Caffarena, E. R., & Costabel, M. D. (2021). How does α1Histidine102 affect the binding of modulators to α1β2γ2 GABAA receptors? Molecular insights from in silico experiments. Physical Chemistry Chemical Physics, 23(6), 3993-4006. https://doi.org/10.1039/D0CP05081D
    1. Artemenko, A. G., Kuz'Min, V. E., Muratov, E. N., Polishchuk, P. G., Borisyuk, I. Y., & Golovenko, N. Y. (2009). Influence of the structure of substituted benzodiazepines on their pharmacokinetic properties. Pharmaceutical Chemistry Journal, 43(8), 454-462. https://doi.org/10.1007/s11094-009-0332-x

LinkOut - more resources