In silico prioritisation of EDN1 missense variants identifies mature endothelin-1 substitutions with predicted receptor-binding effects

Endothelin-1 (ET-1) plays a major role in endothelial function and early vascular ageing (EVA). Although regulatory EDN1 variations have been investigated, it is unclear how missense mutations in the mature ET-1 peptide impact endothelin receptor binding. In this study, we aim to present a systematic in-silico prioritisation framework for EDN1 missense variants and generate structure-based hypotheses for substitutions in the mature ET-1 peptide that may disturb endothelin receptor binding. EDN1 nsSNPs from Ensembl/dbSNP were CADD/REVEL-filtered and assessed by standard pathogenicity, stability, and conservation/accessibility predictors using various tools, followed by short MD simulation. Out of 218 missense variants, integration of predictors identified 15 damaging nsSNPs, with 10 demonstrating consistent destabilisation. Four mutations correspond to the mature peptide: S4W, E10Q, C11R, and V12D. Compared to wild-type, all four showed reduced predicted ETBR binding, approximately 16–17% smaller interfaces, and a decrease in H-bonds. C11R exhibited the most significant disruption. S4W and E10Q resulted in intermediate effects, while V12D demonstrated the least disruption. STRING identified endothelin/renin–angiotensin and kinin-NO modules associated with vasoconstriction, blood pressure regulation, and ECM remodelling. Overall, these variants are computationally prioritised candidates for targeted functional validation.