Docking and molecular dynamics studies on triclosan derivatives binding to FabI

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.

Do Go Chasing Waterfalls: Enoyl Reductase (FabI) in Complex with Inhibitors Stabilizes the Tetrameric Structure and Opens Water Channels

“…Meanwhile, the monomer simulations showed disordered movements of the SBL and active site (Figure ). This conformation diversity was previously observed, to a lesser extent, in shorter simulations (50 ns), where the SBL assumed different folding profiles (α-helix or 3-10 helix) . The relevance of these states is also corroborated by structural information from other organisms’ crystal structures, such as Burkholderia pseudomallei and A.…”

Molecular Dynamics Simulations in Drug Discovery and Pharmaceutical Development

“…The MM-PB(GB)SA approach has been applied in a number of studies, including the development of anticancer compounds [222][223][224], antibacterial [225][226][227], antiviral [228][229][230][231][232] and antiparasitic drugs [233][234][235], as well as antipsychotics [236,237]. These methods are also often applied to understand and analyze the binding mode and key interactions of small molecules [238,239] as well as peptide [240,241] and protein ligands [242] at their targets.…”

Ligand‐ and Structure‐Based Approaches of Escherichia coli FabI Inhibition by Triclosan Derivatives: From Chemical Similarity to Protein Dynamics Influence

“…Yang and collaborators (2017) have already analysed the structural potential of triclosan derivatives by interpreting 50 ns long MD simulations with several TCL derivatives . They have shown that the loop covering the active site can assume structured conformation upon ligand binding.…”

“…Additionally, in the same work, it was reported the absence of π‐π interaction between the inactive compound 23 and the twin tyrosine residues, which partially agrees with our observations regarding the stabilisation importance (Figure B). According to Yang, mostly hydrophobic residues favourably contributed to the binding energy, namely Leu100, Met159, Ala196, Ala197, Ile200, Phe203. This amino‐acid set agrees with our CSM's suggestion that hydrophobic chemical features are relevant to discern differences in the biological activity.…”