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Insight into human protease activated receptor-1 as anticancer target by molecular modelling

A N Hidayat1, E Aki-Yalcin2, M Beksac3

  • 1a Bioinformatics Department , Ankara University , Ankara , Turkey.

SAR and QSAR in Environmental Research
|October 27, 2015
PubMed

Insights

New benzoxazole and benzamide compounds show significant inhibitory activity against Protease-activated receptor 1 (PAR1). This receptor is implicated in cancer progression and metastasis, suggesting potential therapeutic applications.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • Protease-activated receptor 1 (PAR1) is a key target in cancer, particularly in metastasis.
  • PAR1 overexpression correlates with elevated ß-catenin levels, influencing cancer cell phenotypes like proliferation and differentiation.
  • PAR1 signaling pathways, including the PAR1-Gα(13)-DVL axis, are implicated in cancer progression.

Purpose of the Study:

  • To investigate PAR1 expression in multiple myeloma plasma cells.
  • To evaluate the in vitro inhibitory activity of novel benzoxazole (XT2B) and benzamide (XT5) derivatives against PAR1.
  • To analyze the binding mechanisms of these compounds using molecular docking studies.

Main Methods:

  • Flow cytometry was used to analyze PAR1 expression on plasma cells from newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM) patients.
  • In vitro MTT assays were performed to assess the inhibitory effects of XT2B and XT5 on PAR1.
  • Autodock Vina, HYDE binding assessment, and neural network (NN) scoring functions were employed for molecular docking and validation.

Main Results:

  • PAR1 expression was analyzed in CD38+138+ plasma cells from NDMM (n=46) and RRMM (n=45) patients.
  • Benzoxazole (XT2B) and benzamide (XT5) derivatives demonstrated significant in vitro inhibitory activity against PAR1.
  • Docking studies provided insights into the binding mechanisms of the novel compounds with PAR1, validated by HYDE and NN scoring.

Conclusions:

  • The study highlights the potential of targeting PAR1 in multiple myeloma.
  • Novel benzoxazole and benzamide derivatives exhibit promising PAR1 inhibitory activity.
  • Molecular docking studies support the potential of these compounds as PAR1 inhibitors for cancer therapy.
Keywords:
PAR1 antagonistanticancerbenzamidebenzoxazolemolecular docking

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