Insight into human protease activated receptor-1 as anticancer target by molecular modelling.
Protease-activated receptor 1 (PAR1) has been established as a promising target in many diseases, including various cancers. Strong evidence also suggests its role in metastasis. It is proved experimentally that PAR1 can induce numerous cell phenotypes, i.e. proliferation and differentiation. A strong link between PAR1 gene overexpression and high levels of ß-catenin was suggested by a study of the PAR1-Gα(13)-DVL axis in ß-catenin stabilization in cancers. An in vitro study was carried out to analyze PAR1 expression by flow cytometry on CD38+138+ plasma cells obtained from patients either at diagnosis (n: 46) (newly diagnosed multiple myeloma (NDMM)) or at relapse (n: 45) (relapsed/refractory multiple myeloma (RRMM)) and compared with the controls. Our previously synthesized benzoxazole (XT2B) and benzamide (XT5) derivatives were tested with in vitro 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, which revealed significant inhibitory activity on PAR1. We provide docking studies using Autodock Vina of these newly tested compounds to compare with the known PAR1 inhibitors in order to examine the binding mechanisms. In addition, the docking results are validated using HYDE binding assessment and a neural network (NN) scoring function.
a Bioinformatics Department , Ankara University , Ankara , Turkey.
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AN
Hidayat
b Pharmaceutical Chemistry Department , Ankara University , Ankara , Turkey.
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Aki-Yalcin
c Internal Medicine Department , Ankara University , Ankara , Turkey.
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Beksac
d Myeloma Institute, University of Arkansas for Medical Sciences , Arkansas , USA.
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E
Tian
e Levine Cancer Institute, Carolinas Healthcare , Charlotte , USA.
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Usmani
b Pharmaceutical Chemistry Department , Ankara University , Ankara , Turkey.
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Ertan-Bolelli
b Pharmaceutical Chemistry Department , Ankara University , Ankara , Turkey.
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Yalcin
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry* / Q000494:pharmacology; D001583:Benzoxazoles / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D062105:Molecular Docking Simulation; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D016571:Neural Networks, Computer; D010950:Plasma Cells / Q000187:drug effects / Q000201:enzymology; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D044463:Receptor, PAR-1 / Q000737:chemistry* / Q000378:metabolism; D012008:Recurrence; D010975:Platelet Aggregation Inhibitors
D000970:Antineoplastic Agents; D001549:Benzamides; D001583:Benzoxazoles; D044463:Receptor, PAR-1; D010975:Platelet Aggregation Inhibitors
PAR1 antagonist; anticancer; benzamide; benzoxazole; molecular docking