Chemical inhibition of fatty acid synthase: molecular docking analysis and biochemical validation in ocular cancer cells

Abstract

anti-cancer therapeutics. The ocular cancer, retinoblastoma cells were treated with fatty acid synthase (FASN) enzyme inhibitors: cerulenin, triclosan and orlistat. The IC 50 and dose-dependent sensitivity of cancer cells to FASN inhibitors decrease in biologic enzyme activity, and cell morphology alterations were analysed. Molecular interactions of enzyme-inhibitor complexes were studied by molecular modelling and docking simulations. The crystal structures of ketoacyl synthase (PDB ID:3HHD) (cerulenin) and thioesterase (PDB ID:2PX6) (orlistat) domains of human FASN were utilized for docking, while for the non-crystallised human FASN enoyl reductase domain (triclosan), homology model was built and used for docking. All three inhibitors showed significant binding energy indicating stable complex formation with their respective FASN subunits. The predicted Ki value of the FASN inhibitors corroborated well with their corresponding anti-cancer effects.

Recent Evidence Regarding Triclosan and Cancer Risk

“…Henry and Fair’s results were based on only one day of exposure, whereas Liu et al observed reduced viability and a decreasing IC 50 in MCF-7 cells across four days [23,26]. This decrease in IC 50 has also been observed in the studies examining retinoblastoma cells over 96 hours [27,28,29]. Furthermore, Henry and Fair reported slight cytotoxic responses beginning at ~20 μg/mL, within the range observed by both Liu et al and Deepa et al (2012) [26,27].…”

Crystal Structure of the Human Fatty Acid Synthase Enoyl-Acyl Carrier Protein-Reductase Domain Complexed with Triclosan Reveals Allosteric Protein-Protein Interface Inhibition

“…However, in our structure, the hER TCL binding site is located away from the active site at the protein-pro- (38). The TCL binding energy in our allosteric site is estimated to be approximately Ϫ12 kcal/mol, indicating that the allosteric binding site might be more energetically favorable.…”

“…TCL Inhibition Mode-TCL inhibition of FAS was initially believed to act as a traditional active site inhibitor, similar to bacterial ER (38). However, in our structure, the hER TCL binding site is located away from the active site at the protein-pro- (38).…”

“…Regardless of the debate, little is known about the mode of FAS inhibition for TCL. A docking study of TCL binding in an ER domain homology model (38) based on the full-length porcine FAS (pFAS) crystal structure (42) was performed previously; however, no experimental structural data regarding TCL binding to hER are currently available.…”

Studies on New Delhi Metallo-Beta-Lactamse-1 producing Acinetobacter baumannii isolated from donor swab in a tertiary eye care centre, India and structural analysis of its antibiotic binding interactions

“…Semi-flexible docking was done in which protein was kept as rigid and the ligands as flexible [35]. For all the ligands, the possible torsion angles were set to rotate freely.…”