In silico investigation of lactone and thiolactone inhibitors in bacterial quorum sensing using molecular modeling

TL;DR

This study uses molecular modeling to understand how lactone and thiolactone compounds inhibit bacterial quorum sensing, revealing why lactones are more effective and guiding future inhibitor design.

Contribution

It provides computational insights into the binding mechanisms of lactone and thiolactone QS inhibitors, explaining their differing activities and aiding in the design of new inhibitors.

Findings

Lactone inhibitors show higher binding affinity than thiolactones.

Electrostatic interactions are key to inhibitory activity.

MD simulations confirm stability of lactone complexes.

Abstract

In the present study, the origin of the anti-quorum sensing (QS) activities of several members of a recently synthesized and in vitro tested class of lactone and thiolactone based inhibitors were computationally investigated. Docking and molecular dynamic (MD) simulations and binding free energy calculations were carried out to reveal the exact binding and inhibitory profiles of these compounds. The higher in vitro activity of the lactone series relative to their thiolactone isosteres was verified based on estimating the binding energies, the docking scores and monitoring the stability of the complexes produced in the MD simulations. The strong electrostatic contribution to the binding energies may be responsible for the higher inhibitory activity of the lactone with respect to the thiolactone series. The results of this study help to understand the anti-QS properties of lactone-based inhibitors and provide important information that may assist in the synthesis of novel QS inhibitors.