Structure-Based Identification and Binding Mode Analysis of Potential COQ8A (ADCK3) Inhibitors Using AutoDock Vina and AlphaFold3

Résumé fourni par la source

ADCK3 (COQ8A) is a key regulatory protein required for maintaining the stability and activity of the coenzyme Q (CoQ) biosynthetic machinery. Deficiency or dysfunction of ADCK3 can impair CoQ10 biosynthesis, resulting in reduced mitochondrial electron transport efficiency and cellular energy production. In this study, we investigated the binding affinity and binding modes of multiple experimentally validated ligands within the ADCK3 binding pocket. Comparative analyses were performed using both AlphaFold 3 (AF3)-predicted protein–ligand complexes and AutoDock Vina docking simulations. The binding scores and predicted interaction patterns obtained from these approaches were evaluated to identify common structural and physicochemical characteristics associated with favorable ligand binding. In addition, structure-based pharmacophore analysis was conducted to characterize the key molecular features required for ADCK3 recognition. Among the sixteen selected active ligands, six compounds were prioritized for detailed analysis based on their predicted binding performance. Binding mode analysis revealed that ligand stabilization within the ADCK3 pocket was primarily mediated through a combination of hydrogen-bonding interactions, hydrophobic contacts, π-π stacking interactions, and, in some cases, halogen bonding interactions with residues lining the binding cavity. Collectively, these findings provide insight into the molecular determinants governing ligand recognition by ADCK3 and highlight key binding features that may serve as valuable considerations in future ADCK3-targeted drug discovery and lead optimization efforts.

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