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Discovery of small molecule sirt1 activator using high-throughput virtual screening, molecular dynamics simulation, molecular mechanics generalized born/surface area (MM/GBSA) calculation, and biological evaluation

  • Yiqiang An
  • Chen Meng
  • Qingqing Chen
  • Jian GaoEmail author
Original Research
  • 28 Downloads

Abstract

Sirt1, namely silent information regulator 1, belongs to a highly conserved family of NAD+-dependent deacetylase which is involved in innumerable human disorders such as obesity, type 2 diabetes, cancer, and aging. Combined high-throughput virtual screening, molecular dynamics simulation, MM/GBSA free energy calculation, and MM/GBSA free energy decomposition analysis approaches were utilized for identification of sirt1 activators. Four compounds with diverse chemical scaffold were retrieved as hits based on docking score and clustering analysis. Our simulations indicated that compound y040-6677 had the highest binding free energies, which could form one hydrogen bond with the residue Asn226. Compound y040-6677 could tightly plug into the hydrophobic allosteric site of sirt1 via strong interaction with the residues Leu215, Thr219, Gln222, Ile223, and Asn226, which were obtained from the MM/GBSA free energy decomposition. These simulation results were consistent with the in vivo enzymatic assay, which implied that compound y040-6677 had a comparable sirt1 activation compared with the reference molecule SRT1720. We hope that compound y040-6677 might represent a promising chemical scaffold for further development of novel sirt1 activators.

Keywords

Sirt1 activator High-throughput virtual screening Molecular dynamics simulation 

Notes

Acknowledgements

This work was supported by National Natural Science Foundation of China (NSFC No. 21708033), Six Talent Peaks Project in Jiangsu Province (grant number YY-046), and the Qinglan Project of Jiangsu Province of China.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

44_2019_2479_MOESM1_ESM.pdf (337 kb)
Supplementary Material

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouPR China
  2. 2.Department of Pharmacy, The First Hospital of JiaxingThe First Affiliated Hospital of Jiaxing UniversityJiaxingPR China

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