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

Abstract

Enoyl‐acyl carrier protein reductase (FabI) is the limiting step to complete the elongation cycle in type II fatty acid synthase (FAS) systems and is a relevant target for antibacterial drugs. E. coli FabI has been employed as a model to develop new inhibitors against FAS, especially triclosan and diphenyl ether derivatives. Chemical similarity models (CSM) were used to understand which features were relevant for FabI inhibition. Exhaustive screening of different CSM parameter combinations featured chemical groups, such as the hydroxy group, as relevant to distinguish between active/decoy compounds. Those chemical features can interact with the catalytic Tyr156. Further molecular dynamics simulation of FabI revealed the ionization state as a relevant for ligand stability. Also, our models point the balance between potency and the occupancy of the hydrophobic pocket. This work discusses the strengths and weak points of each technique, highlighting the importance of complementarity among approaches to elucidate EcFabI inhibitor's binding mode and offers insights for future drug discovery.

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

“…Previous FabI inhibitor studies employed shorter monomeric simulations focusing on protein–ligand interactions. ,,− For instance, our group carried out short molecular dynamics of 1 μs (5 × 200 ns), studying Ec FabI monomers with diphenyl ether derivatives, where we established a relationship between protein–ligand interactions and compound potency. Previous Sa FabI full tetramer simulations (four individual chains with 25 ns each) identified structural determinants, such as the folding of H6/H7, that led to differences in the ligand residence time …”

“…Protein structures were prepared by adding hydrogen atoms and fixing missing side chains using Protein Preparation Wizard (Maestro 2021.4, Schrödinger LLC, New York, NY, USA). Ionization states of amino acids were optimized with PROPKA (pH 7.4, Schrödinger), and as for the ligands, TCL and MUT were considered phenolates …”

“…Ionization states of amino acids were optimized with PROPKA (pH 7.4, Schrodinger), and as for the ligands, TCL and MUT were considered phenolates. 28 2.2. Molecular Dynamics Simulations.…”

“…The coordinates for TCL (PDB ID: 1QG6 10 ), MUT (MD frame previously reported 28 ), and AFN (PDB ID: 4FS3) were retrieved from respectives referenced structures. 8 The coordinates of NADP + (S. aureus) and NAD + (E. coli) were retrieved from the template structures.…”

“…This cooperativity is supported by the increased ligand affinity depending on FabI’s oligomerization state and the observation of TCL-resistant mutants displaying substitutions in the dimer interface . Until now, computational studies have focused only on the FabI monomeric state or employed subrelevant timescales to study large conformational changes. − …”