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Structural Insight into the Interactions between Structurally Similar Inhibitors and SIRT6

Shuang Zhao1, Yan-Yan Zhu1, Xiao-Yu Wang1

  • 1Department of Mathematics and Physics, Shanghai University of Electric Power, Shanghai 20090, China.

International Journal of Molecular Sciences
|April 15, 2020
PubMed

Insights

Scutellarin, a natural compound, shows potential as a Sirtuin 6 (SIRT6) inhibitor for cancer treatment. Molecular dynamics simulations revealed its binding mechanism, offering a new avenue for drug discovery from Traditional Chinese Medicine.

Area of Science:

  • Biochemistry and Molecular Biology
  • Pharmacology
  • Computational Chemistry

Background:

  • Sirtuin 6 (SIRT6) is implicated in various cancers, including colon and rectal adenocarcinoma, yet effective drugs are lacking.
  • Understanding atomic-level interactions between SIRT6 and inhibitors is crucial for developing targeted therapies.
  • Natural products offer a promising source for identifying novel anticancer agents.

Purpose of the Study:

  • To investigate the potential of Scutellarin, a natural compound from Traditional Chinese Medicine (TCM), as a Sirtuin 6 (SIRT6) inhibitor.
  • To elucidate the molecular interactions between SIRT6 and structurally similar inhibitors at the atomic level.
  • To explore the utility of Traditional Chinese Medicine (TCM) resources for discovering novel cancer therapeutics.

Main Methods:

  • Molecular dynamics (MD) simulations were employed to study the interactions between SIRT6 and potential inhibitors.
  • Conformational analysis of Compound 9 (Asinex ID: BAS13555470) guided the selection of Scutellarin.
  • Binding modes and key interacting residues were identified through simulation analysis.

Main Results:

  • Scutellarin demonstrated a similar binding mode to SIRT6 as other inhibitors, interacting with key residues like Leu9, Phe64, Val115, His133, and Trp188.
  • Hydrophobic and π-stacking interactions were identified as critical for the binding of inhibitors to SIRT6.
  • The study identified Scutellarin as a novel potential inhibitor of SIRT6, highlighting its therapeutic promise.

Conclusions:

  • The study reveals the interactive mechanism between SIRT6 and its inhibitors at an atomic level.
  • Scutellarin is proposed as a new potential inhibitor for Sirtuin 6 (SIRT6)-related cancers.
  • This research provides a novel strategy for identifying potential anticancer drugs from Traditional Chinese Medicine (TCM) resources.
Keywords:
SIRT6binding siteshydrophobic interactionsinhibitormolecular dynamics simulationnature moleculescutellarinπ–stacking interactions

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