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Scaffold Hopping Computational Approach for Searching Novel β-Lactamase Inhibitors

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Abstract—

We present a novel computational ligand-based virtual screening approach with scaffold hopping capabilities for the identification of novel inhibitors of β-lactamases which confer bacterial resistance to β‑lactam antibiotics. The structures of known β-lactamase inhibitors were used as query ligands, and a virtual in silico screening a database of 8 million drug-like compounds was performed in order to select the ligands with similar shape and charge distribution. A set of numerical descriptors was used such as chirality, eigen spectrum of matrices of interatomic distances and connectivity together with higher order moment invariants that showed their efficiency in the field of pattern recognition but have not yet been employed in drug discovery. The developed scaffold-hopping approach was applied for the discovery of analogues of four allosteric inhibitors of serine β-lactamases. After a virtual in silico screening, the effect of two selected ligands on the activity of TEM type β-lactamase was studied experimentally. New non-β-lactam inhibitors were found that showed more effective inhibition of β-lactamases compared to query ligands.

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Funding

The work on production of recombinant β-lactamase TEM-171 and inhibitory analysis has been supported by the Russian Science Foundation (project 15-14-00014-C). Virtual screening of the inhibitors was supported by the EMBL Interdisciplinary Postdocs (EIPOD) fellowship programme under Marie Skłodowska-Curie COFUND (grant no. 291 772) from the European Commission for the postdoctoral fellowship.

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Authors and Affiliations

  1. European Molecular Biology Laboratory (EMBL), c/o DESY, Notkestr. 85, 22607, Hamburg, Germany

    D. A. Beshnova, C. Carolan & V. S. Lamzin

  2. UT Southwestern Medical Center, 6000 Harry Hines Blvd, 75235, Dallas, TX, United States

    D. A. Beshnova

  3. International Civil Aviation Organization (ICAO), 999 Robert-Bourassa Boulevard, H3C 5H7, Montréal, Québec, Canada

    C. Carolan

  4. Chemistry Department, Moscow State University, 119991, Moscow, Russia

    V. G. Grigorenko, M. Yu. Rubtsova & A. M. Egorov

  5. European Molecular Biology Laboratory, Meyerhofstraße 1, 69117, Heidelberg, Germany

    E. Gbekor & J. Lewis

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  1. D. A. Beshnova
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  2. C. Carolan
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  3. V. G. Grigorenko
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  4. M. Yu. Rubtsova
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  7. V. S. Lamzin
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  8. A. M. Egorov
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Correspondence to A. M. Egorov.

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Beshnova, D.A., Carolan, C., Grigorenko, V.G. et al. Scaffold Hopping Computational Approach for Searching Novel β-Lactamase Inhibitors. Biochem. Moscow Suppl. Ser. B 14, 127–135 (2020). https://doi.org/10.1134/S199075082002002X

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