title: Free energy calculations on the binding of novel thiolactomycin derivatives to E. coli fatty acid synthase I.
abstract: Finding novel antibiotics to combat the rise of drug resistance in harmful bacteria is of enormous importance for human health. Computational drug design can be employed to aid synthetic chemists in the search for new potent inhibitors. In recent years, molecular dynamics based free energy calculations have emerged as a useful tool to accurately calculate receptor binding affinities of novel or modified ligands. While being significantly more demanding in computational resources than simpler docking algorithms, they can be employed to obtain reliable estimates of the effect individual functional groups have on protein-ligand complex binding constants. Beta-ketoacyl [acyl carrier protein] synthase I, KAS I, facilitates a critical chain elongation step in the fatty acid synthesis pathway. Since the bacterial type II lipid synthesis system is fundamentally different from the mammalian type I multi-enzyme complex, this enzyme represents a promising target for the design of specific antibiotics. In this work, we study the binding of several recently synthesized derivatives of the natural KAS I inhibitor thiolactomycin in detail based on atomistic modeling. From extensive thermodynamic integration calculations the effect of changing functional groups on the thiolactone scaffold was determined. Four ligand modifications were predicted to show improved binding to the E. coli enzyme, pointing the way towards the design of thiolactomycin derivatives with binding constants in the nanomolar range.
authors.affiliation: Institut für Physikalische Chemie, Abteilung Theoretische Chemische Biologie, Universität Karlsruhe, KIT, Kaiserstr. 12, 76131 Karlsruhe, Germany. thomas.steinbrecher@kit.edu
authors.forename: Thomas
authors.initials: T
authors.lastname: Steinbrecher
authors.forename: David A
authors.initials: DA
authors.lastname: Case
authors.forename: Andreas
authors.initials: A
authors.lastname: Labahn
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D013876:Thiophenes / Q000737:chemistry / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D007527:Isoenzymes; D008024:Ligands; D013876:Thiophenes; C035068:thiolactomycin; C078182:beta-ketoacyl-acyl carrier protein synthase I; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase