Affiliations 

  • 1 Faculty of Pharmacy , Sanata Dharma University , Depok, Sleman 55282 , Yogyakarta , Indonesia
  • 2 Faculty of Pharmacy , Padjadjaran University , Jatinangor, Sumedang 45363 , West Java , Indonesia
  • 3 Chemistry Department, Faculty of Mathematics and Natural Sciences , Padjadjaran University , Jatinangor, Sumedang 45363 , West Java , Indonesia
  • 4 Pharmacy Program, Faculty of Science and Technology , Ma Chung University , Malang 65151 , Indonesia
  • 5 Cancer Chemoprevention Research Center, Faculty of Pharmacy , Gadjah Mada University , Sekip Utara 55281 , Yogyakarta , Indonesia
  • 6 Faculty of Pharmacy and Medical Sciences , AlAhliyya Amman University , Amman 19328 , Jordan
  • 7 Pharmaceutical Technology Department, School of Pharmaceutical Sciences and USM-RIKEN Centre for Ageing Science (URICAS) , Universiti Sains Malaysia , 11800 Minden , Pulau Pinang , Malaysia
J Chem Inf Model, 2020 01 27;60(1):349-359.
PMID: 31825614 DOI: 10.1021/acs.jcim.9b00630

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.