Scaffold hopping computational approach for searching novel β-lactamase inhibitors

   
Beshnova D.A.1, Carolan C.2, Grigorenko V.G.3, Rubtsova M.Yu.3, Gbekor E.4, Lewis J.4, Lamzin V.S.5, Egorov A.M.3

1. European Molecular Biology Laboratory, c/o DESY, Hamburg, Germany; UT Southwestern Medical Center, Dallas, TX, United States
2. European Molecular Biology Laboratory, c/o DESY, Hamburg, Germany; International Civil Aviation Organization (ICAO), Montreal, Quebec, Canada
3. Chemistry Department, M.V. Lomonosov Moscow State University, Moscow, Russia
4. European Molecular Biology Laboratory, Heidelberg, Germany
5. European Molecular Biology Laboratory, c/o DESY, Hamburg, Germany
Section: Experimental Study
DOI: 10.18097/PBMC20196506468      PubMed Id: 31876517
Year: 2019  Volume: 65  Issue: 6  Pages: 468-476
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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Keywords: beta-lactamases, virtual screening, scaffold hopping, ligands, inhibitors, antibiotic resistance
Citation:

Beshnova, D. A., Carolan, C., Grigorenko, V. G., Rubtsova, M. Yu., Gbekor, E., Lewis, J., Lamzin, V. S., Egorov, A. M. (2019). Scaffold hopping computational approach for searching novel β-lactamase inhibitors. Biomeditsinskaya khimiya, 65(6), 468-476.
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