Unveiling the biophysical basis of DYRK kinase family isoform selectivity mechanism of Abemaciclib using computational approaches.

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) play crucial roles in regulating cell growth and brain development. Dysregulation of these kinases is linked to disorders like Down syndrome and cancers. The selective inhibition of DYRK1A over other isoforms remains a significant challenge due to their high structural similarity. This study investigates the selectivity of Abemaciclib, an FDA-approved CDK4/6 inhibitor known to target DYRK1A, against other DYRK family isoforms. We employed molecular docking and molecular dynamics simulations, coupled with the Molecular Mechanics Poisson-Boltzmann Surface Area method, to evaluate the selectivity profile of Abemaciclib. Results showed that it binds strongest to DYRK1B, followed by DYRK1A, DYRK4, DYRK3 and DYRK2, which is validated with the statistical analysis. Enhanced selectivity for DYRK1B arises from stronger van der Waals and electrostatic interactions. Hydrophobic contacts and hydrogen bonds, especially within the kinase's hinge region, help stabilize the complex. Notably, Leu241 in DYRK1A and its identical residues in other isoforms play a pivotal role in these stabilizing interactions. Key residue differences, like Phe170, Glu239 and His285 in DYRK1A, contribute to specific interactions that underpin the molecular binding pattern. By identifying conserved and isoform-specific interactions, our study provides valuable insights for the rational design of potent and selective DYRK inhibitors.