Ligand- and Structure-Based Approaches of Escherichia coli FabI Inhibition by Triclosan Derivatives: From Chemical Similarity to Protein Dynamics Influence.
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.
['Kronenberger|Thales|T|0000-0001-6933-7590', 'de Oliveira Fernades|Philipe|P|0000-0001-8089-2958', 'Drumond Franco|Isabella|I|', 'Poso|Antti|A|0000-0003-4196-4204', 'Gonçalves Maltarollo|Vinícius|V|0000-0001-9675-5907']
D000595:Amino Acid Sequence D000900:Anti-Bacterial Agents D001665:Binding Sites D004353:Drug Evaluation, Preclinical D050753:Enoyl-(Acyl-Carrier-Protein) Reductase (NADH) D004791:Enzyme Inhibitors D004926:Escherichia coli D029968:Escherichia coli Proteins D054889:Fatty Acid Synthase, Type II D006801:Humans D008024:Ligands D008958:Models, Molecular D011485:Protein Binding D011487:Protein Conformation D013329:Structure-Activity Relationship D014260:Triclosan
triclosan enoyl-acyl carrier protein reductase (FabI) chemical similarity models molecular dynamics