DEVELOPMENT OF APPROACHES TO MOLECULAR MODELING OF THE INTERACTION OF BIOLOGICALLY ACTIVE COMPONENTS OF HUMIC SUBSTANCES WITH BETA-LACTAMASES ON THE EXAMPLE OF HUMIC-LIKE LOW-MOLECULAR WEIGHT ANALOGUES
UDK 577(11+151+181)
Abstract
β-Lactamase inhibitors are used to protect betalactam antibiotics from the action of antibiotic resistant bacteria. However, due to the emergence of resistance to β-lactam inhibitors, the search for new non-betalactam inhibitors is an urgent task. In this work, natural humic substances (HS) are considered as a new source of beta-lactamase inhibitors. We previously reported on the ability of coal humic acids and their narrow fractions to inhibit TEM-1 β-lactamases. The purpose of this work was to study the mechanism of interaction between the molecular components of humic substances using molecular modeling. The selection of humic-like molecules was carried out using the dereplication method based on the known inhibitory activity of the HS fraction and its molecular composition as determined by high-resolution mass spectrometry. Modeling of the interaction of selected molecules with beta-lactamase protein was carried out using docking and molecular dynamics methods using Chimera v.1.15 software and Amber14. As a result of dereplication, 156 unique structures were identified, of which three were selected. The modeling results showed that the most likely mechanism of interaction of HS with beta-lactamase is non-competitive inhibition as a result of binding to the allosteric site of the protein. In addition, nonspecific aggregation on the protein surface is possible, which also explains the synergistic effect of HS with respect to sulbactam, which might be sterically blocked in the active site of betalactamase. The prospects of using the dereplication method for studying the molecular mechanisms of the biological activity of humic substances are shown.
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