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Covalent docking of selected boron-based serine beta-lactamase inhibitors

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Abstract

AmpC β-lactamase is a hydrolytic enzyme conferring resistance to β-lactam antibiotics in multiple Gram-negative bacteria. Therefore, identification of non-β-lactam compounds able to inhibit the enzyme is crucial for the development of novel antibacterial therapies. In general, AmpC inhibitors have to engage the highly solvent-exposed catalytic site of the enzyme. Therefore, understanding the implications of ligand–protein induced-fit and water-mediated interactions behind the inhibitor-enzyme recognition process is fundamental for undertaking structure-based drug design process. Here, we focus on boronic acids, a promising class of beta-lactamase covalent inhibitors. First, we optimized a docking protocol able to reproduce the experimentally determined binding mode of AmpC inhibitors bearing a boronic group. This goal was pursued (1) performing rigid and flexible docking calculations aiming to establish the role of the side chain conformations; and (2) investigating the role of specific water molecules in shaping the enzyme active site and mediating ligand protein interactions. Our calculations showed that some water molecules, conserved in the majority of the considered X-ray structures, are needed to correctly predict the binding pose of known covalent AmpC inhibitors. On this basis, we formalized our findings in a docking and scoring protocol that could be useful for the structure-based design of new boronic acid AmpC inhibitors.

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Acknowledgments

We acknowledge the CINECA and the Regione Lombardia award under the LISA initiative, for the availability of high performance computing resources and support. Financial support was obtained by the Italian Ministry of Education and Research through the Flagship (PB05) “InterOmics”.

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  1. Jacopo Sgrignani

    Present address: Institute of research in Biomedicine (IRB), Via Vincenzo Vela 6, 6500, Bellinzona, Switzerland

Authors and Affiliations

  1. Dipartimento di Scienze Farmaceutiche, Sezione di Chimica Farmaceutica “Pietro Pratesi”, Università degli Studi di Milano, Via L. Mangiagalli 25, 20133, Milan, Italy

    Beatrice Novati & Giovanni Grazioso

  2. ICRM-CNR, Via Mario Bianco 9, 20131, Milan, Italy

    Jacopo Sgrignani & Giorgio Colombo

Authors
  1. Jacopo Sgrignani
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  2. Beatrice Novati
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  3. Giorgio Colombo
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  4. Giovanni Grazioso
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Correspondence to Giorgio Colombo or Giovanni Grazioso.

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Sgrignani, J., Novati, B., Colombo, G. et al. Covalent docking of selected boron-based serine beta-lactamase inhibitors. J Comput Aided Mol Des 29, 441–450 (2015). https://doi.org/10.1007/s10822-015-9834-7

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