2-Hexylthio-β,γ-CH2-ATP is an effective and selective NTPDase2 inhibitor.

Abstract

NTPDase2 catabolizes nucleoside triphosphates and consequently, through the interaction of nucleotides with P2 receptors, controls multiple biological responses. NTPDase2 inhibitors could modulate responses induced by nucleotides in thrombosis, inflammation, cancer, etc. Here we developed a set of ATP analogues as potential NTPDase inhibitors and identified a subtype-selective and potent NTPDase2 inhibitor, 2-hexylthio-β,γ-methylene-ATP, 2. Analogue 2 was stable to hydrolysis by NTPDase1, -2, -3, and -8. It inhibited hNTPDase2 with Ki 20 μM, while only marginally (5-15%) inhibiting NTPDase1, -3, and -8. Homology models of hNTPDase1 and -2 were constructed. Docking and subsequent linear interaction energy (LIE) simulations provided a correlation with r2=0.94 between calculated and experimental inhibition data for the triphosphate analogues considered in this work. The origin of selectivity of 2 for NTPDase2 over NTPDase1 is the thiohexyl moiety of 2 which is favorably located within a hydrophobic pocket, whereas in NTPDase1 it is exposed to the solvent.

• Authors: Irina Gillerman, Joanna Lecka, Luba Simhaev, Mercedes N Munkonda, Michel Fausther, Mireia Martín-Satué, Hanoch Senderowitz, Jean Sévigny, Bilha Fischer
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 57 Issue 14 Pg. 5919-34 (Jul 24 2014) ISSN: 1520-4804 [Electronic] United States
• PMID: 24972256 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-hexylthio-beta,gamma-methylene-adenosine triphosphate
• Enzyme Inhibitors
• Adenosine Triphosphate
• Adenosine Triphosphatases
• ectoATPase

Topics

• Adenosine Triphosphatases (antagonists & inhibitors, metabolism)
• Adenosine Triphosphate (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Dose-Response Relationship, Drug
• Drug Design
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Humans
• Models, Molecular
• Molecular Structure
• Structure-Activity Relationship