Elucidating binding modes of zuonin A enantiomers to JNK1 via in silico methods

•Zuonin A enantiomer binding modes were predicted using docking and MD.•Zuonin A enantiomers are predicted to bind the same conserved JNK recognition site.•Zuonin A enantiomers are predicted to have their own unique binding modes.

Aberrant c-Jun N-terminal kinase (JNK) signaling is associated with a number of diseases, including neurological conditions and cancer. Enantiomers of the lignan zuonin A, (−)-zuonin A and (+)-zuonin A bind isoforms of JNK with similar affinity and disrupt protein-protein interactions at JNK's D-recruitment site. Thus, they are of interest as lead non-ATP competitive inhibitors of the JNKs. While (−)-zuonin A inhibits the activity of JNK toward c-Jun by 80% when saturating, (+)-zuonin A only inhibits by 15%. Molecular docking and molecular dynamics simulations were performed to gain a better understanding of how these inhibitors interact with JNK. The results of this study provide new insight into potential binding modes for (−)-zuonin A and suggest that (−)-zuonin A interacts with JNK via an induced fit mechanism near the highly conserved φA-X-φB recognition site. Binding of (+)-zuonin A to JNK displays no such dynamic feature. The different binding modes may help explain differences in the inhibitory properties of the enantiomers although further experimental work would be necessary to fully confirm this interpretation.

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