Binding modes of the metabolites docosahexaenoic acid, eicosapentaenoic acid, and eicosapentaenoic acid ethyl ester from Caulerpa racemosa as COX-2 inhibitors revealed via metabolomics and molecular dynamics

A total of 116 metabolites of Caulerpa racemosa were identified. However, only three (DHA, EPA, and EPAS) were found to have high anti-inflammatory potential, with Pa scores ranging from 0.764 to 0,827. The inhibition constant (Ki) and binding energy interactions with COX-2 revealed by DHA (−8.83 kcal/mol: 0.338 μM), EPA (−8.35 kcal/mol: 0.763 μM), EPAS (−8.05 kcal/mol: 1.25 μM). They were used to bind to the fundamental residues of COX-2 (TYR 348, VAL 349, LEU 384, TYR 385, and TRP 387). The result of molecular dynamics showed that DHA, EPA, and EPAS had high stability while interacting with COX-2 in 310 K. The stabilities were 1.8 Å for DHA from 60 Ns to 200 Ns, 2.0 Å for EPA from 75 Ns to 200 Ns, and 2.2 Å for EPAS from 100 Ns to 200 Ns. Additionally, the potential energy of DHA (−1.069.250 eV) was higher compared with that of EPA (−1.069.247 eV) and EPAS (−1.069.220 eV). This data shows that DHA, EPA, and EPAS could stably inhibit COX-2 by blocking the transcriptional regulation of COX-2 via TYR348, VAL349, LEU384, TYR385, and TRP387.