Multifaceted Role of Matrix Metalloproteases on Human Diseases

Roy, Subhasish; Pramanik, Asmita; Chakraborti, Tapati; Chakraborti, Sajal

doi:10.1007/978-981-10-3162-5_2

Cited by 1 publication

(3 citation statements)

References 109 publications

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“…The characters of EWG in 7, 8, and 9 are observed by an adjoining pyrimidine ring to NH−SO 2 . In addition, the steric character is increased by the addition of the methyl (8) and dimethyl group (9) to the pyrimidine ring, thus contributing to more pronounced inhibition toward MMP9 activity. The attachment of halogen EWG such as chloro (3) and fluoro (4) did not improve the binding with PEX9 as shown in the docking study, where only one hydrogen bond interaction with GLN154 is stabilizing the interaction between the ligands and PEX9, thus contributing to the higher free energy of binding.…”

Section: ■ Discussionmentioning

confidence: 99%

“…7,8 The genomic structure of MMP9 is composed of the propeptide and a catalytic domain, which is bridged by SH-Zn, followed by three fibronectins, which are linked to the terminal hemopexin-like (PEX9) domain. 9,10 The enzyme is activated by disconnecting the SH-Zn bridge (called a cysteine switch) to interact with the substrate. 11,12 Therefore, by interrupting this interaction using peptidomimetics or small molecules, the progress of angiogenesis and cell migration could be well controlled.…”

Section: ■ Introductionmentioning

confidence: 99%

“…MMP9 is one of the MMP subfamilies, classified as gelatinase that degrades the extracellular matrix (ECM). It also has gelatin as the substrate for the enzyme activity. , The genomic structure of MMP9 is composed of the propeptide and a catalytic domain, which is bridged by SH-Zn, followed by three fibronectins, which are linked to the terminal hemopexin-like (PEX9) domain. , The enzyme is activated by disconnecting the SH-Zn bridge (called a cysteine switch) to interact with the substrate. , Therefore, by interrupting this interaction using peptidomimetics or small molecules, the progress of angiogenesis and cell migration could be well controlled . Unfortunately, many MMP9 inhibitors failed in the clinical trials due to the presence of adverse drug side effects (ADS) such as musculoskeletal syndrome .…”

Section: Introductionmentioning

confidence: 99%

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Arylamide as Potential Selective Inhibitor for Matrix Metalloproteinase 9 (MMP9): Design, Synthesis, Biological Evaluation, and Molecular Modeling

Hariono

Nuwarda

Yusuf

et al. 2019

J. Chem. Inf. Model.

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Previous studies have reported that compounds bearing an arylamide linked to a heterocyclic planar ring have successfully inhibited the hemopexin-like domain (PEX9) of matrix metalloproteinase 9 (MMP9). PEX9 has been suggested to be more selectively targeted than MMP9’s catalytic domain in a degrading extracellular matrix under some pathologic conditions, especially in cancer. In this study, we aim to synthesize and evaluate 10 arylamide compounds as MMP9 inhibitors through an enzymatic assay as well as a cellular assay. The mechanism of inhibition for the most active compounds was investigated via molecular dynamics simulation (MD). Molecular docking was performed using AutoDock4.0 with PEX9 as the protein model to predict the binding of the designed compounds. The synthesis was carried out by reacting aniline derivatives with 3-bromopropanoyl chloride using pyridine as the catalyst at room temperature. The MMP9 assay was conducted using the FRET-based MMP9 kits protocol and gelatin zymography assay. The cytotoxicity assay was done using the MTT method, and the MD simulation was performed using AMBER16. Assay on MMP9 demonstrated activities of three compounds (2, 7, and 9) with more than 50% inhibition. Further inhibition on MMP9 expressed by 4T1 showed that two compounds (7 and 9) inhibited its gelatinolytic activity more than 50%. The cytotoxicity assay against 4T1 cells results in the inhibition of the cell growth with an EC50 of 125 μM and 132 μM for 7 and 9, respectively. The MD simulation explained a stable interaction of 7 and 9 in PEX9 at 100 ns with a free energy of binding of −8.03 kcal/mol and −6.41 kcal/mol, respectively. Arylamides have potential effects as selective MMP9 inhibitors in inhibiting breast cancer cell progression.

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Section: ■ Discussionmentioning

confidence: 99%