title: In silico investigation of lavandulyl flavonoids for the development of potent fatty acid synthase-inhibitory prototypes.
abstract: Inhibition of fatty acid synthase (FAS) is regarded as a sensible therapeutic strategy for the development of optimal anti-cancer agents. Flavonoids exhibit potent anti-neoplastic properties.
  
  
  
  The MeOH extract of Sophora flavescens was subjected to chromatographic analyses such as VLC and HPLC for the purification of active flavonoids. The DP4 chemical-shift analysis protocol was employed to investigate the elusive chirality of the lavandulyl moiety of the purified polyphenols. Induced Fit docking protocols and per-residue analyses were utilized to scrutinize structural prerequisites for hampering FAS activity. The FAS-inhibitory activity of the purified flavonoids was assessed via the incorporation of [3H] acetyl-CoA into palmitate.
  
  
  
  Six flavonoids, including lavandulyl flavanones, were purified and evaluated for FAS inhibition. The lavandulyl flavanone sophoraflavanone G (2) exhibited the highest potency (IC50of 6.7±0.2μM), which was more potent than the positive controls. Extensive molecular docking studies revealed the structural requirements for blocking FAS. Per-residue interaction analysis demonstrated that the lavandulyl functional group in the active flavonoids (1-3 and 5) significantly contributed to increasing their binding affinity towards the target enzyme.
  
  
  
  This research suggests a basis for the in silico design of a lavandulyl flavonoid-based architecture showing anti-cancer effects via enhancement of the binding potential to FAS.
  
  
  
  FAS inhibition by flavonoids and their derivatives may offer significant potential as an approach to lower the risk of various cancer diseases and related fatalities. In silico technologies with available FAS crystal structures may be of significant use in optimizing preliminary leads.
authors.affiliation: Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Department of Chemistry, Yale University, New Haven, CT 06520, United States; Chemical Biology Institute, Yale University, West Haven, CT 06516, United States.
authors.forename: Joonseok
authors.initials: J
authors.lastname: Oh
authors.affiliation: Department of BioMolecular Sciences, Division of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States.
authors.forename: Haining
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Chemistry, Yale University, New Haven, CT 06520, United States; Chemical Biology Institute, Yale University, West Haven, CT 06516, United States.
authors.forename: Hyun Bong
authors.initials: HB
authors.lastname: Park
authors.affiliation: Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States.
authors.forename: Daneel
authors.initials: D
authors.lastname: Ferreira
authors.affiliation: College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
authors.forename: Gil-Saeng
authors.initials: GS
authors.lastname: Jeong
authors.affiliation: Department of BioMolecular Sciences, Division of Pharmacognosy, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, United States.
authors.forename: Mark T
authors.initials: MT
authors.lastname: Hamann
authors.affiliation: Department of BioMolecular Sciences, Division of Medicinal Chemistry, School of Pharmacy, The University of Mississippi, University, MS 38677, United States; Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, United States. Electronic address: rjd@olemiss.edu.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Doerksen
authors.affiliation: College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea. Electronic address: mkna@cnu.ac.kr.
authors.forename: MinKyun
authors.initials: M
authors.lastname: Na
mesh_terms: D000072283:A549 Cells; D000818:Animals; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D020134:Catalytic Domain; D016923:Cell Death / Q000187:drug effects; D002645:Chickens; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D000072417:Protein Domains; D066244:Proton Magnetic Resonance Spectroscopy; D029909:Sophora / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D005419:Flavonoids; D064429:Fatty Acid Synthases
keywords: DP4 chemical-shift analysis; Fatty acid synthase; Induced Fit docking; Lavandulyl flavonoids; Per-residue analysis; Sophora flavescens