Three new acrylic acid derivatives from Achillea mellifolium as potential thymidine phosphorylase inhibitor: molecular docking and MD simulation studies

Discovery of potent inhibitors of thymidine phosphorylase (TP) can offer appropriate approach in cancer treatment owing to it's over expression in various human tumors compared to normal healthy tissues. Thymidine phosphorylase alongside 2-deoxy-D-ribose are reported as promoters of unwanted angiogenesis in cancerous cells. In this study, three new acrylic acid derivatives (1-3) have been isolated from ethyl acetate fraction of Achillea mellifolium. The characterization of these compounds (1-3) was done using UV, IR, 1 D and 2 D-NMR spectroscopy (¹H-NMR, ¹³C-NMR, HMBC, NOESY) and mass spectrometry. The structure of these acrylic acid derivatives were ethyl (E)-3-((1S,5R)-5-methoxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)acrylate (1), methyl (E)-3-((1S,5R)-5-methoxy-2,6,6-trimethyl-4-oxocyclohex-2-en-1-yl)acrylate (2) and (4S,6R)-6-methoxy-3,5,5-trimethyl-4-((E)-3-oxobut-1-en-1-yl)cyclohex-2-en-1-one (3). Thymidine phosphorylase (TP) inhibition studies showed compound 3 as most active inhibitor of TP with IC₅₀ value 57.81 ± 3.41 while compound 1 and 2 showed IC₅₀ value as 158.9 ± 0.97 and 89.92 ± 0.37, respectively. In addition, molecular docking studies of compound (1-3) were performed to shed light on their binding interaction patterns for binding into active pocket of TP. Similarly, all compounds (1-3) were evaluated for their anti-oxidant potential showing anti-oxidant activities with IC₅₀ value ranging from 49.73 ± 0.41 to 79.81 ± 0.39. Later, these compound-protein (1-3) complexes were further subjected to MD simulations studies (50 ns) involving root mean square deviation, root mean square fluctuation, and secondary structure analysis to explore their binding mode stability inside active pocket. Communicated by Ramaswamy H. Sarma.