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In silico investigation of lavandulyl flavonoids for the development of potent fatty acid synthase-inhibitory prototypes
- Oh, Joonseok, Liu, Haining, Park, Hyun Bong, Ferreira, Daneel, Jeong, Gil-Saeng, Hamann, Mark T., Doerksen, Robert J., Na, MinKyun
- Biochimica et biophysica acta 2017 v.1861 no.1 pp. 3180-3188
- Sophora flavescens, acetyl coenzyme A, antineoplastic activity, antineoplastic agents, binding capacity, crystal structure, fatty acids, fatty-acid synthase, flavanones, high performance liquid chromatography, inhibitory concentration 50, methanol, molecular models, neoplasms, polyphenols, prototypes, risk, stereoisomerism
- 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 (IC50 of 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.