Novel statin derivatives as non-competitive inhibitors of human adenylate kinase 1: synthesis, enzyme inhibition, molecular docking, and biological studies.

Adenylate kinases (AKs) are a family of conserved phosphotransferases essential for maintaining cellular energy homeostasis through the interconversion of adenine nucleotides. Recent studies have revealed that AKs contribute to various pathophysiological processes beyond energy metabolism, particularly in inflammation, cardiovascular diseases, and neurodegeneration. Despite their emerging therapeutic relevance, efforts to develop selective AK inhibitors remain limited. Existing inhibitors, such as dinucleoside polyphosphates (e.g., Ap5A), act competitively but have low selectivity, limited bioavailability, and may cause off-target effects because they closely resemble natural nucleotides. These limitations highlight the need for novel AK inhibitors with improved pharmacological profiles and alternative mechanisms of action. In our study, we synthesized new statin derivatives and evaluated their impact on human adenylate kinase 1 (hAK1) activity. Enzymatic assays confirmed that these compounds act as non-competitive inhibitors of hAK1. Molecular docking was employed to explore AK1 binding and elucidate the mechanism of non-competitive inhibition. In addition, their interactions with human and bovine serum albumin were investigated using fluorescence spectroscopy. The study also evaluated the effects of these compounds on HMG-CoA reductase activity, providing insights into their potential biological relevance. Furthermore, the impact of statin derivatives on HepG2 cell viability, HDL uptake, and the activity of membrane-bound adenylate kinase were assessed.