Adenosine deaminase - A target for new piperazine derivatives

Abstract

The level of adenosine deaminase (ADA) activity increases in pathological effusions. Therefore, the concentration of its substrate, anti-inflammatory adenosine, decreases, thereby aggravating inflammation. Hence, the quest for ADA inhibiting compounds is an actual problem in medicine and pharmacology. This work describes the inhibition of bovine ADA by new synthesized piperazine compounds. 15 compounds were screened; IC₅₀ values for 5 more potent ones of them were between 3.4 and 98.6 μg/ml. The inhibition of activity of intracellular and ecto- forms of ADA by the most effective "compound 1" was of competitive nature. For these two forms of enzyme, the inhibition constants, K_i (1.5 and 115 μM) and IC₅₀ values (6.5 and 480 μM), respectively, differed by nearly two orders. The constant of bimolecular interaction K_SV between "compound 1" and the tryptophan residues in ADA was estimated in fluorescence quenching study as of 0.145 ± 0.027 μM. Finally, the molecular interactions between "compound 1" and the bovine enzyme ADA were highlighted through molecular docking studies.

Keywords: Adenosine deaminase isoforms; Enzyme inhibition; Fluorescence quenching; Molecular docking; Protein-ligand interaction.