Identification of potential allosteric inhibitors-modulators for the heterodimer CDC34-UBC protein-protein complex

To identify potential allosteric modulators targeting the allosteric site of the CDC34-UBC protein-protein interaction (PPI) complex, the current study employs advanced in-silico methods, including similarity searches, molecular docking, pharmacokinetics, and molecular dynamics (MD) simulation. A similarity search of 26,318 allosteric kinase inhibitors from ChemDiv was performed with the seven known standard molecules. Highly similar molecules were docked into the allosteric site of CDC34-UBC, and the resulting higher-affinity molecules were assessed for pharmacokinetics and absolute binding affinity. By following the above workflow, a total of four drug-like chemical entities, namely E612-1064, G681-0837, C076-0187, and K284-1783, were identified as potential hits for CDC34-UBC. The comparative analysis with one of the standard molecules (ASD06112004) revealed either better or comparable binding affinity towards CDC34-UBC. The binding energies from PLANTS, AutoDock Vina, and K_Deep were found to be -112.15, -10.10, and - 8.70 kcal/mol; -110.35, -10.20, and - 9.61 kcal/mol; -95.69, -10.20, and - 10.31 kcal/mol; and - 96.11, -10.00, and - 10.10 kcal/mol for E612-1064, G681-0837, C076-0187, and K284-1483, respectively. Several parameters indicated that the protein backbone did not deviate by more than 2.18 Å from its initial position in any frame of the 100 ns MD simulations, indicating stability with the proposed molecules. The MM-GBSA energies for E612-1064, G681-0837, C076-0187, and K284-1483 were - 17.80, -34.27, -18.80, and - 9.04 kcal/mol, respectively, indicating that the molecules were potential in nature. Hence, selected molecules may act as allosteric kinase inhibitors targeting the CDC34-UBC complex, paving the way for new therapies for diseases linked to disruptions of the ubiquitin-proteasome system.

The online version contains supplementary material available at 10.1007/s13205-026-04777-0.