Insights into interactions of scytonemin and its derivatives with dipeptidyl peptidase-IV

Abstract

Dipeptidyl peptidase-IV (DPP-IV) is a promising target for treating diabetes, which is a major global healthcare challenge. Existing DPP-IV inhibitor drugs have been associated with side effects, hence there is a pressing need to discover therapeutic alternatives. Algae have emerged as an important source of structurally diverse natural metabolites with pharmaceutical activities. This study aims to combine systematic in-silico screening with detailed molecular interactions analysis, and in-vitro DPP-IV enzyme inhibition assay to identify best algal metabolite as inhibitor. Potential allosteric surface binding sites were predicted in DPP-IV. To gain insight into interactions, conformation stability and flexibility upon ligand binding were analyzed. Virtual screening of 69 metabolites identified 12 ligands scoring better than positive control drug sitagliptin (−8.73 ± 0.37 kcal/mol) including luteolin-7-glucoside, hesperidin, epigallocatethin, phlorofucofuroeckol B), calothrixin. The highest scoring metabolite was identified as scytonemin (−10.86 ± 0.05 kcal/mol). MMPBSA analysis of interactions between derivatives of scytonemin and DPP-IV revealed differences in binding energy score. Compared to scytonemin (−21.18 ± 2.11 kcal/mol), dimethoxyscytonemin showed improved binding affinity (−26.41 ± 1.93 kcal/mol), whereas tetramethoxyscytonemin and scytonin exhibited reduced energy (−16.93 ± 3.06 kcal/mol and − 12.29 ± 4.24 kcal/mol, respectively). Analysis of scytonemin and its derivatives interactions with amino acid residues in DPP-IV binding site identified Trp-695 and Phe-674 as key residues for binding. Additionally, scytonemin exhibited potent DPP-IV enzyme inhibitory activity (IC<inf>50</inf> = 2.75 ± 1.70 nM). In conclusion, this study identifies that scytonemin has good activity as DPP-IV inhibitor, supporting its potential as antidiabetic therapeutic. © 2026 Elsevier B.V.