Exploring the C‐Terminal Tail Dynamics: Structural and Molecular Perspectives into the Therapeutic Activities of Novel CRMP‐2 Inhibitors, Naringenin and Naringenin‐7‐ O ‐glucuronide, in the Treatment of Alzheimer's Disease

The collapsin response mediator protein (CRMP‐2) is hyperphosphorylated in Alzheimer's disease (AD). These phosphorylation events are mediated by specific kinase proteins, GSK3β and Cdk5, and occur at target phosphorylation sites majorly located at the C‐terminal tail of CRMP‐2. The abilities of naringenin (NAR) and naringenin‐7‐ O ‐glucuronide (NAR‐7‐ O ‐G) to selectively bind CRMP‐2 and reduce its phosphorylation have been previously demonstrated; the molecular interplay between these events remains unresolved. Using computational tools, we unravel the possible mechanisms by which these molecules disrupt CRMP‐2 phosphorylation. Structural and dynamic analyses revealed that while the C‐terminal tail of unbound CRMP‐2 was extended and subtly organized, notable conformational disarray and rigidity characterized this region when bound by NAR and NAR‐7‐ O ‐G. Consequentially, atomistic motions of constituent phosphorylation sites were restricted, indicative of structural occurrences that could distort the accessibility of interactive kinase proteins. A similar pattern was observed at a target phosphorylation site located in the globular domain of CRMP‐2. MM/PBSA analyses revealed that both compounds interacted favorably with CRMP‐2 while crucial residues that enhanced their selective binding include Glu353, Thr349, Lys254, Asp140 and Arg75. These structural insights provide mechanistic events that could contribute towards the structure‐based design of anti‐AD molecules which can bind CRMP2 selectively and alter its phosphorylation process.