Natural compounds as angiogenic enzyme thymidine phosphorylase inhibitors: In vitro biochemical inhibition, mechanistic, and in silico modeling studies


Autoři: Sumaira Javaid aff001;  Muniza Shaikh aff001;  Narjis Fatima aff001;  M. Iqbal Choudhary aff001
Působiště autorů: Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center of Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan aff001;  H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan aff002;  Department of Biochemistry, Faculty of Sciences, King Abdulaziz University, Jeddah, Saudi Arabia aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225056

Souhrn

Natural flora is the richest source of novel therapeutic agents due to their immense chemical diversity and novel biological properties. In this regard, eighteen natural products belonging to different chemical classes were evaluated for their thymidine phosphorylase (TP) inhibitory activity. TP shares identity with an angiogenic protein platelet derived endothelial cell growth factor (PD-ECGF). It assists tumor angiogenesis and is a key player in cancer progression, thus an ideal target to develop anti-angiogenic drugs. Eleven compounds 12, 510, 11, 15, and 18 showed a good to weak TP inhibitory activity (IC50 values between 44.0 to 420.3 μM), as compared to standards i.e. tipiracil (IC50 = 0.014 ± 0.002 μM) and 7-deazaxanthine (IC50 = 41.0 ± 1.63 μM). Kinetic studies were also performed on active compounds, in order to deduce the mechanism of ligand binding to enzyme. To get further insight into receptor protein (enzyme) and ligand interaction at atomic level, in- sillico studies were also performed. Active compounds were finally evaluated for cytotoxicity test against mouse fibroblast (3T3) cell line. Compound 18 (Masoprocol) showed a significant TP inhibitory activity (IC50 = 44.0 ± 0.5 μM). Kinetic studies showed that it inhibits the enzyme in a competitive manner (Ki = 25.6 ± 0.008 μM), while it adopts a binding pose different than the substrate thymidine. It is further found to be non-toxic in MTT cytotoxicity assay. This is the first report on TP inhibitory activity of several natural compounds, some of which may serve as leads for further research towards drug the development.

Klíčová slova:

Angiogenesis – Cytotoxicity assay – Enzyme inhibitors – Hydrogen bonding – MTT assay – Phosphorylases – Thymidines – Coumarins


Zdroje

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2019 Číslo 11