In silico investigation of lavandulyl flavonoids for the development of potent fatty acid synthase-inhibitory prototypes

Abstract

Background 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. Methods 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. Results Six flavonoids, including lavandulyl flavanones, were purified and evaluated for FAS inhibition. The lavandulyl flavanone sophoraflavanone G (2) exhibited the highest potency (IC50 of 6.7 ± 0.2 μM), 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. Conclusion 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. General significance 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.

Review on target domains and natural compound‐based inhibitors of fatty acid synthase for anticancer drug discovery

“…As FASN is a lipid synthesis protein, it also plays an important role in obesity (Oh et al, 2017; Tan et al, 2019). Orlistat, an anti‐obesity drug is also proven to be an effective FASN inhibitor (Pemble et al, 2007).…”

“…Hydrogen bonding is observed between C‐4 carbonyl oxygen and sulphonyl hydrogen of Cys161, 7‐OH and carbonyl oxygen of Ser 265 and carboxylate oxygen of Asp254. The negative vander waal interactions with hydrophobic amino acid residues and hydrogen bonding highly enhance the binding affinity in the KS domain (Oh et al, 2017). Luteolin ( 13 ), a flavonoid present in celery, thyme, green peppers, chamomile tea, etc., has a structure that resembles P13K inhibitor showing an IC 50 value of 2.5 µg/ml against FASN.…”

New Insights into Polyphenols in Plants as Potential Modulators of Atherosclerosis by Acting on Lipoprotein Lipase: In Silico Molecular Docking and In Vitro Studies

“…Pancreatic lipase belongs to the lipase superfamily, similar to LPL, and has been reported to be directly regulated by polyphenols . For example, previous studies have shown that polyphenols derived from berry and tea elicit anti-lipase activity, , and this finding was further supported by Sergent et al Previous studies have also suggested that polyphenols alter lipid metabolism via multiple mechanisms, including decreased levels of cholesterol and fatty acid synthesis and reduced production of reactive oxygen species (ROS), − consequently leading to decreased risks of CVD. However, few studies have examined the effect of polyphenols on LPL activity.…”

Identification of novel antilipogenic agents targeting fatty acid biosynthesis through structure‐based virtual screening

“…Concerning the KS domain, several inhibitors have been reported in the literature . For examples, inhibitors of the KS domain are structurally related to flavonoids such as morin and luteolin . Other described KS inhibitors are the thiolactone thiolactomycin, the epoxyde cerulenin, the lactone C75 or are related to hydroxyquinolinone or isochromanone derivatives (Scheme ).…”