Free energy calculations on the binding of novel thiolactomycin derivatives to E. coli fatty acid synthase i

Thomas Steinbrecher, David Case, Andreas Labahn

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3446-3453
Number of pages8
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number11
DOIs
StatePublished - Jun 1 2012

Fingerprint

Fatty Acid Synthases
Escherichia coli
Free energy
Ligands
Derivatives
Functional groups
Enzymes
Anti-Bacterial Agents
Drug Design
Molecular Dynamics Simulation
Thermodynamics
Drug Resistance
Scaffolds
Pharmaceutical Preparations
Molecular dynamics
Elongation
Bacteria
Fatty Acids
Health
thiolactomycin

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

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Free energy calculations on the binding of novel thiolactomycin derivatives to E. coli fatty acid synthase i. / Steinbrecher, Thomas; Case, David; Labahn, Andreas.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 11, 01.06.2012, p. 3446-3453.

Research output: Contribution to journalArticle

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