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Korea Genome Organization (한국유전체학회)
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Cinnamic acid derivatives as potential matrix metalloproteinase-9 inhibitors: molecular docking and dynamics simulations

  • Mohammad Hossein Malekipour (Dental Students Research Center, School of Dentistry, Isfahan University of Medical Sciences) ;
  • Farzaneh Shirani (Dental Research Center, Dental Research Institute, Department of Operative Dentistry, School of Dentistry, Isfahan University of Medical Sciences) ;
  • Shadi Moradi (Department of Medical Immunology, School of Medicine, Hamadan University of Medical Science) ;
  • Amir Taherkhani (Research Center for Molecular Medicine, Hamadan University of Medical Science)
  • Received : 2022.12.19
  • Accepted : 2023.01.12
  • Published : 2023.03.31
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Abstract

Matrix metalloproteinase-9 (MMP-9) is a zinc and calcium-dependent proteolytic enzyme involved in extracellular matrix degradation. Overexpression of MMP-9 has been confirmed in several disorders, including cancers, Alzheimer's disease, autoimmune diseases, cardiovascular diseases, and dental caries. Therefore, MMP-9 inhibition is recommended as a therapeutic strategy for combating various diseases. Cinnamic acid derivatives have shown therapeutic effects in different cancers, Alzheimer's disease, cardiovascular diseases, and dental caries. A computational drug discovery approach was performed to evaluate the binding affinity of selected cinnamic acid derivatives to the MMP-9 active site. The stability of docked poses for top-ranked compounds was also examined. Twelve herbal cinnamic acid derivatives were tested for possible MMP-9 inhibition using the AutoDock 4.0 tool. The stability of the docked poses for the most potent MMP-9 inhibitors was assessed by molecular dynamics (MD) in 10 nanosecond simulations. Interactions between the best MMP-9 inhibitors in this study and residues incorporated in the MMP-9 active site were studied before and after MD simulations. Cynarin, chlorogenic acid, and rosmarinic acid revealed a considerable binding affinity to the MMP-9 catalytic domain (ΔGbinding < -10 kcal/ mol). The inhibition constant value for cynarin and chlorogenic acid were calculated at the picomolar scale and assigned as the most potent MMP-9 inhibitor from the cinnamic acid derivatives. The root-mean-square deviations for cynarin and chlorogenic acid were below 2 Å in the 10 ns simulation. Cynarin, chlorogenic acid, and rosmarinic acid might be considered drug candidates for MMP-9 inhibition.

Keywords

Acknowledgement

The authors would like to thank the Dental Research Center, Isfahan University of Medical Sciences, Isfahan- Iran, and the Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan - Iran, for their support.

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