Inhibition of Cyclooxygenase-2 and Thymidylate Synthase by Dietary Sphingomyelins: Insights from DFT and Molecular Docking Studies

Abstract

Inhibition of cyclooxygenase-2 (COX-2) and thymidylate Synthase (TS) enzymes play prominent chemopreventive and chemotherapeutic roles in colorectal cancer studies. Basic computational investigation on the inhibition of these enzymes by sphingomyelin (SM) derivatives was carried out in silico using Density Functional Theory (DFT) and molecular docking studies. Interactions between SM with unsaturated fatty acids, COX-2 and TS were compared with that of 5-Fluorouracil (5-FU) and Celecoxib, the standard anti-colorectal cancer drugs. The results showed that SM with alpha-linoleic acid derivative possesses the highest HOMO (-4.70 eV) and lowest LUMO (0.09 eV) energies, which may enhance their interactions with their target receptors. All SM molecules, irrespective of the fatty acid nature have lower binding affinities, (ΔG = -5.5 to - 6.8 kcal/mol) against COX-2 than Celecoxib (-10.1 kcal/mol), indicating that the standard COX-2 inhibitor is much stronger than the natural SM. However, some of the natural SM are stronger inhibitors of thymidylate synthase than the standard drug, 5-FU, with SM having alpha-linoleic acid derivative (ΔG = - 6.2 kcal/mol) higher than 5-FU (ΔG = -5.28 kcal/mol), but lower than that of the active drug metabolite, 5-FdUMP (ΔG = - 7.4 kcal/mol). These ligand-protein interactions were all feasible and spontaneous.