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Ligand‐ and Structure‐Based Approaches of Escherichia coli FabI Inhibition by Triclosan Derivatives: From Chemical Similarity to Protein Dynamics Influence
Author(s) -
Kronenberger Thales,
Oliveira Fernades Philipe,
Drumond Franco Isabella,
Poso Antti,
Gonçalves Maltarollo Vinícius
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900415
Subject(s) - triclosan , acyl carrier protein , drug discovery , escherichia coli , biology , docking (animal) , stereochemistry , ligand (biochemistry) , in silico , enzyme , chemistry , biochemistry , combinatorial chemistry , computational biology , biosynthesis , medicine , receptor , nursing , pathology , gene
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 Ec FabI inhibitor's binding mode and offers insights for future drug discovery.