title: 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: Department of Chemistry, Bar-Ilan University , Ramat-Gan 52900, Israel.
authors: Irina
authors: I
authors: Gillerman
authors: Joanna
authors: J
authors: Lecka
authors: Luba
authors: L
authors: Simhaev
authors: Mercedes N
authors: MN
authors: Munkonda
authors: Michel
authors: M
authors: Fausther
authors: Mireia
authors: M
authors: Martín-Satué
authors: Hanoch
authors: H
authors: Senderowitz
authors: Jean
authors: J
authors: Sévigny
authors: Bilha
authors: B
authors: Fischer
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: C000592444:2-hexylthio-beta,gamma-methylene-adenosine triphosphate; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; C027201:ectoATPase