Journal of Computer-Aided Molecular Design

, Volume 32, Issue 4, pp 547–557 | Cite as

Insight into the molecular mechanism of yeast acetyl-coenzyme A carboxylase mutants F510I, N485G, I69E, E477R, and K73R resistant to soraphen A

  • Jian GaoEmail author
  • Li Liang
  • Qingqing Chen
  • Ling Zhang
  • Tonghui HuangEmail author


Acetyl-coenzyme A carboxylases (ACCs) is the first committed enzyme of fatty acid synthesis pathway. The inhibition of ACC is thought to be beneficial not only for diseases related to metabolism, such as type-2 diabetes, but also for infectious disease like bacterial infection disease. Soraphen A, a potent allosteric inhibitor of BC domain of yeast ACC, exhibit lower binding affinities to several yeast ACC mutants and the corresponding drug resistance mechanisms are still unknown. We report here a theoretical study of binding of soraphen A to wild type and yeast ACC mutants (including F510I, N485G, I69E, E477R, and K73R) via molecular dynamic simulation and molecular mechanics/generalized Born surface area free energy calculations methods. The calculated binding free energies of soraphen A to yeast ACC mutants are weaker than to wild type, which is highly consistent with the experimental results. The mutant F510I weakens the binding affinity of soraphen A to yeast ACC mainly by decreasing the van der Waals contributions, while the weaker binding affinities of Soraphen A to other yeast ACC mutants including N485G, I69E, E477R, and K73R are largely attributed to the decreased net electrostatic (ΔEele + ΔGGB) interactions. Our simulation results could provide important insights for the development of more potent ACC inhibitors.


Acetyl-coenzyme A carboxylases Biotin carboxylase Soraphen A Drug resistance Molecular dynamics simulation 



This study was funded by National Natural Science Foundation of China (NSFC No. 21708033), China Postdoctoral Science Foundation funded project (Grants No. 2017M611916), Natural Science Foundation of Jiangsu Province (Grants No. BK20171184), Scientific Research Foundation for Talented Scholars of Xuzhou Medical College (Grant No. D2014008), and Science and Technology project of Xuzhou (Grant No. KC16SG249).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

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Supplementary material 1 (DOCX 1011 KB)


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© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouPeople’s Republic of China

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