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Docking and molecular dynamics studies on triclosan derivatives binding to FabI

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Abstract

FabI, enoyl-ACP reductase (ENR), is the rate-limiting enzyme in the last step for fatty acids biosynthesis in many bacteria. Triclosan (TCL) is a commercial bactericide, and as a FabI inhibitor, it can depress the substrate (trans-2-enoyl-ACP) binding with FabI to hinder the fatty acid synthesis. The structure-activity relationship between TCL derivatives and FabI protein has already been acknowledged, however, their combination at the molecular level has never been investigated. This paper uses the computer-aided approaches, such as molecular docking, molecular dynamics simulation, and binding free energy calculation based on the molecular mechanics/Poisson-Bolzmann surface area (MM/PBSA) method to illustrate the interaction rules of TCL derivatives with FabI and guide the development of new derivatives. The consistent data of the experiment and corresponding activity demonstrates that electron-withdrawing groups on side chain are better than electron-donating groups. 2-Hydroxyl group on A ring, promoting the formation of hydrogen bond, is vital for bactericidal effect; and the substituents at 4-position of A ring, 2′-position and 4′-position of B ring benefit antibacterial activity due to forming a hydrogen bond or stabilizing the conformation of active pocket residues of receptor. While the substituents at 3′-position and 5′-position of B ring destroy the π-π stacking interaction of A ring and NAD+ which depresses the antibacterial activity. This study provides a new sight for designing novel TCL derivatives with superior antibacterial activity.

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Acknowledgements

The authors acknowledge financial support from the National Natural Science Foundation of China. (No. 21176194, 21476174)

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Authors and Affiliations

  1. Tianjin University of Technology, TianJin, 300384, China

    Xuyun Yang, Junrui Lu, Ming Ying, Jiangbei Mu, Peichun Li & Yue Liu

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  1. Xuyun Yang
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  2. Junrui Lu
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Correspondence to Junrui Lu.

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Yang, X., Lu, J., Ying, M. et al. Docking and molecular dynamics studies on triclosan derivatives binding to FabI. J Mol Model 23, 25 (2017). https://doi.org/10.1007/s00894-016-3192-9

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  • DOI: https://doi.org/10.1007/s00894-016-3192-9

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