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


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.


Sirt1 activator High-throughput virtual screening Molecular dynamics simulation 



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


  1. Afshar G, Murnane JP (1999) Characterization of a human gene with sequence homology to Saccharomyces cerevisiae SIR2. Gene 234:161–168CrossRefGoogle Scholar
  2. Blander G, Guarente L (2004) The Sir2 family of protein deacetylases. Annu Rev Biochem 73:417–435CrossRefGoogle Scholar
  3. Cao D, Wang M, Qiu X, Liu D, Jiang H, Yang N, Xu RM (2015) Structural basis for allosteric, substrate-dependent stimulation of SIRT1 activity by resveratrol. Genes Dev 29:1316–1325CrossRefGoogle Scholar
  4. Case DA, Cheatham 3rd TE, Darden T, Gohlke H, Luo R, Merz Jr. KM, Onufriev A, Simmerling C, Wang B, Woods RJ (2005) The Amber biomolecular simulation programs. J Comput Chem 26:1668–1688CrossRefGoogle Scholar
  5. Cerqueira NM, Gesto D, Oliveira EF, Santos-Martins D, Bras NF, Sousa SF, Fernandes PA, Ramos MJ (2015) Receptor-based virtual screening protocol for drug discovery. Arch Biochem Biophys 582:56–67CrossRefGoogle Scholar
  6. Chen F, Liu H, Sun H, Pan P, Li Y, Li D, Hou T (2016) Assessing the performance of the MM/PBSA and MM/GBSA methods. 6. Capability to predict protein-protein binding free energies and re-rank binding poses generated by protein-protein docking. Phys Chem Chem Phys 18:22129–22139CrossRefGoogle Scholar
  7. Cheng W, Wang JF, Yang CX, Wu L, Yin Q, Liu H, Fu ZJ (2016) Intrathecal injection of resveratrol attenuates burn injury pain by activating spinal sirtuin 1. Pharmacogn Mag 12:S201–S205CrossRefGoogle Scholar
  8. Dai H, Case AW, Riera TV, Considine T, Lee JE, Hamuro Y, Zhao H, Jiang Y, Sweitzer SM, Pietrak B, Schwartz B, Blum CA, Disch JS, Caldwell R, Szczepankiewicz B, Oalmann C, Yee Ng P, White BH, Casaubon R, Narayan R, Koppetsch K, Bourbonais F, Wu B, Wang J, Qian D, Jiang F, Mao C, Wang M, Hu E, Wu JC, Perni RB, Vlasuk GP, Ellis JL (2015) Crystallographic structure of a small molecule SIRT1 activator-enzyme complex. Nat Commun 6:7645CrossRefGoogle Scholar
  9. Gao J, Liang L, Chen Q, Zhang L, Huang T (2018) Insight into the molecular mechanism of yeast acetyl-coenzyme A carboxylase mutants F510I, N485G, I69E, E477R, and K73R resistant to soraphen A. J Comput Aided Mol Des 32:547–557CrossRefGoogle Scholar
  10. Gao J, Zhang Y, Chen H, Chen Q, Feng D, Zhang L, Li C (2019) Computational insights into the interaction mechanism of transcription cofactor vestigial-like protein4 binding to TEA domain transcription factor 4 by molecular dynamics simulation and molecular mechanics generalized Born/surface area) calculation. J Biomol Struct Dyn 37:2538–2545CrossRefGoogle Scholar
  11. Ge LQ, Li CZ, Wang ZR, Zhang Y, Chen L (2017) Suppression of oxidative stress and apoptosis in electrically stimulated neonatal rat cardiomyocytes by resveratrol and underlying mechanisms. J Cardiovasc Pharmacol 70:396–404PubMedGoogle Scholar
  12. He WJ, Wang YY, Zhang MZ, You L, Davis LS, Fan H, Yang HC, Fogo AB, Zent R, Harris RC, Breyer MD, Hao CM (2010) Sirt1 activation protects the mouse renal medulla from oxidative injury. J Clin Investig 120:1056–1068CrossRefGoogle Scholar
  13. Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE, E SY, Lamming DW, Pentelute BL, Schuman ER, Stevens LA, Ling AJY, Armour SM, Michan S, Zhao H, Jiang Y, Sweitzer SM, Blum CA, Disch JS, Ng PY, Howitz KT, Rolo AP, Hamuro Y, Moss J, Perni RB, Ellis JL, Vlasuk GP, Sinclair DA (2013) Evidence for a common mechanism of SIRT1 regulation by allosteric activators. Science 339:1216–1219CrossRefGoogle Scholar
  14. Kitada M, Kume S, Takeda-Watanabe A, Kanasaki K, Koya D (2013) Sirtuins and renal diseases: relationship with aging and diabetic nephropathy. Clin Sci 124:153–164CrossRefGoogle Scholar
  15. Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham 3rd TE (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897CrossRefGoogle Scholar
  16. Kumar A, Chauhan S (2016) How much successful are the medicinal chemists in modulation of SIRT1: a critical review. Eur J Med Chem 119:45–69CrossRefGoogle Scholar
  17. Liu YW, Hao YC, Chen YJ, Yin SY, Zhang MY, Kong L, Wang TY (2018) Protective effects of sarsasapogenin against early stage of diabetic nephropathy in rats. Phytother Res 32:1574–1582CrossRefGoogle Scholar
  18. Longo VD, Kennedy BK (2006) Sirtuins in aging and age-related disease. Cell 126:257–268CrossRefGoogle Scholar
  19. Lu Q, Ji XJ, Zhou YX, Yao XQ, Liu YQ, Zhang F, Yin XX (2015) Quercetin inhibits the mTORC1/p70S6K signaling-mediated renal tubular epithelial-mesenchymal transition and renal fibrosis in diabetic nephropathy. Pharmacol Res 99:237–247CrossRefGoogle Scholar
  20. Sacconnay L, Carrupt PA, Nurisso A (2016) Human sirtuins: structures and flexibility. J Struct Biol 196:534–542CrossRefGoogle Scholar
  21. Sun H, Li Y, Tian S, Xu L, Hou T (2014) Assessing the performance of MM/PBSA and MM/GBSA methods. 4. Accuracies of MM/PBSA and MM/GBSA methodologies evaluated by various simulation protocols using PDBbind data set. Phys Chem Chem Phys 16:16719–16729CrossRefGoogle Scholar
  22. Villalba JM, Alcain FJ (2012) Sirtuin activators and inhibitors. Biofactors 38:349–359CrossRefGoogle Scholar
  23. Vyas VK, Goel A, Ghate M, Patel P (2015) Ligand and structure-based approaches for the identification of SIRT1 activators. Chem Biol Interact 228:9–17CrossRefGoogle Scholar
  24. Wakino S, Hasegawa K, Itoh H (2015) Sirtuin and metabolic kidney disease. Kidney Int 88:691–698CrossRefGoogle Scholar
  25. Weiser J, Shenkin PS, Still WC (1999) Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO). J Comput Chem 20:217–230CrossRefGoogle Scholar
  26. Xie J, Zhang XM, Zhang L (2013) Negative regulation of inflammation by SIRT1. Pharmacol Res 67:60–67CrossRefGoogle Scholar
  27. Yorimitsu T, Nair U, Yang ZF, Klionsky DJ (2006) Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281:30299–30304CrossRefGoogle Scholar
  28. Zhou L, Fu L, Lv N, Chen XS, Liu J, Li Y, Xu QY, Huang S, Zhang XD, Dou LP, Wang LL, Li YH, Yu L (2017) A minicircuitry comprised of microRNA-9 and SIRT1 contributes to leukemogenesis in t(8;21) acute myeloid leukemia. Eur Rev Med Pharmacol Sci 21:786–794PubMedGoogle Scholar
  29. Zhu SP, Liu G, Wu XT, Chen FX, Liu JQ, Zhou ZH, Zhang JF, Fei SJ (2013) The effect of phloretin on human gammadelta T cells killing colon cancer SW-1116 cells. Int Immunopharmacol 15:6–14CrossRefGoogle Scholar

Copyright information

© 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

Personalised recommendations