Contact-Network Phenotyping of the CDK Family Reveals Selective Distal C-Lobe Contact Redistribution by Modern CDK5 Inhibitors and a Quantitative Selectivity Landscape against CDK2 and CDK1.

Selective inhibition of CDK5 over CDK1, CDK2, CDK4, and CDK6 remains a central medicinal-chemistry challenge because pocket-centric methods capture local similarity but not full-domain structural phenotypes. Here we introduce kinase-aware contact-network phenotyping, a calculation-light approach that combines systematic Cα contact-map comparison with automated kinase topology annotation across 30 curated CDK crystal structures spanning CDK1, CDK2, CDK3, CDK4, CD5, and CD6 with 21 pairwise comparisons. Three findings emerge. First, the apo CDK5 to selective inhibitor transition (1H4L to 7VDP) produces 33.3% ligand-adjacent gained contacts (13 of 39), compared with 2.8% (1 of 36) for the apo to nonselective transition (1H4L to 1UNL); the apo-anchored ratio of 11.9-fold quantifies the selective-specific reorganization while controlling for generic pocket-occupancy effects, with the largest distance shifts (up to 14.6 Å) concentrated in the distal C-lobe core (residues 221 to 292). Second, the DFG aspartate D144 has the most atypical contact environment in CDK5 by the Miyazawa-Jernigan knowledge-based statistical-potential