Exploring the binding modes of cordycepin to human adenosine deaminase 1 (ADA1) compared to adenosine and 2'-deoxyadenosine.

Cordycepin (3'-deoxyadenosine, abbreviated as COR) from Cordyceps shows a wide range of pharmacological activities, including antioxidant and anticancer effects, therefore representing a potential alternative medicine. However, COR has a short half-life in the human body, where it is metabolized by adenosine deaminase 1 (ADA1). ADA1 helps regulate adenosine levels by deaminating excess adenosine (ADE) and its derivatives, such as 2'-deoxyadenosine (DEO). Understanding binding mechanisms of ADA1 with COR in comparison with its other substrates will play a vital role in improving the bioactivity and lifetime of COR for commercial medicinal use. Recently, the first structure of human ADA1 in complex with DEO was solved. We therefore employed molecular dynamics (MD) simulations to predict structures and dynamics of ADA1 complexing with ADE, DEO, and COR in comparison to a ligand-free (LF) structure. Our data reveal that a large and highly water-exposed binding pocket of ADA1 is responsible for ligand translocation and reorientation. Two possible binding locations (site1 and site2) are identified. The binding affinities of the ligands are ADE > COR > DEO. Furthermore, the movements of two loop regions at the binding pocket entrance, residues 183-193 and 215-230, contribute to gating activity.