The density functional theory calculations are employed to elucidate the adsorption/desorption behaviours of mercaptopurine (MP) and thioguanine (TG) drugs on the gold surfaces, using Au3 and Au4 clusters as model reactants. The PBE functional in combination with the effective core potential cc-pVTZ-PP basis set for gold atoms and cc-pVTZ basis set for nonmetals have been used to investigated geometric structures, thermodynamic parameters and electronic properties of the obtained complexes. The IEF-PCM model with water solvent was used to include the effect of biological environment on the interactions. The computed results show that the binding is dominated by a covelant bond Au−S and by electrostatic effects, namely a hydrogen bond contribution NH∙∙∙Au. In addition, the drug binding to gold clusters is a reversible process and a drug release mechanism was also clarified. Accordingly, the drugs are willing to separate from the gold surface due to either a slight change of pH in tumor cells or the presence of cysteine residues in protein matrices.