Natural Product Neopeltolide as a Cytochrome bc1 Complex Inhibitor: Mechanism of Action and Structural Modification

Journal of Agricultural and Food Chemistry
Xiao-Lei ZhuGuang-Fu Yang

Abstract

The marine natural product neopeltolide was isolated from a deep-water sponge specimen of the family Neopeltidae. Neopeltolide has been proven to be a new type of inhibitor of the cytochrome bc1 complex in the mitochondrial respiration chain. However, its detailed inhibition mechanism has remained unknown. In addition, neopeltolide is difficult to synthesize because of its very complex chemical structure. In the present work, the binding mode of neopeltolide was determined for the first time by integrating molecular docking, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, which showed that neopeltolide is a Qo site inhibitor of the bc1 complex. Then, according to guidance via inhibitor-protein interaction analysis, structural modification was carried out with the aim to simplify the chemical structure of neopeltolide, leading to the synthesis of a series of new neopeltolide derivatives with much simpler chemical structures. The calculated binding energies (Δ Gcal) of the newly synthesized analogues correlated very well ( R2 = 0.90) with their experimental binding free energies (Δ Gexp), which confirmed that the computational protocol was reliable. Compound 45, bearing a diphe...Continue Reading

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Citations

Jan 15, 2020·Current Medicinal Chemistry·Dario MatuljaDean Marković
Jun 27, 2020·Journal of Enzyme Inhibition and Medicinal Chemistry·Serena VeschiAlessandro Cama
Oct 11, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Loana MussoSabrina Dallavalle
May 14, 2021·Bioorganic & Medicinal Chemistry Letters·Yuanyuan ZhangHui Xu
Jul 8, 2021·Bioorganic & Medicinal Chemistry Letters·Min LvHui Xu
Aug 14, 2020·Journal of Agricultural and Food Chemistry·Tao ChenGuang-Fu Yang
Oct 5, 2021·Journal of Agricultural and Food Chemistry·Weizhen WangXili Liu
Oct 29, 2021·Journal of Agricultural and Food Chemistry·Hua LiGuang-Fu Yang

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