Molecular recognition of modified adenine nucleotides by the P2Y₁-receptor. 2. A computational approach

The molecular recognition of C2- or C8-substituted ATP derivatives by the P2Y₁-receptor (P2Y₁-R) is analyzed using ab initio quantum mechanical calculations. Parameters that may determine ligand specificity toward P2Y₁-R were examined on reduced models and correlated with the biochemical data for the parent compounds. These include tautomerism and protonation energy in the gas and aqueous phases, as well as molecular electrostatic potential (MEP) and dipole moment vector. The calculated electronic parameters cannot explain the inactivity of the C8-substituted ATP derivatives, nor the difference in activity among the C2-substituted ATP analogues. These results indicate that neither tautomerism nor changes in the electronic distribution of the adenine ring play a major role in determining binding specificity of adenine nucleotides to the receptor. It is suggested that the higher potency of the C2-substituted ATP derivatives, compared to ATP, might be due to interaction between the C2 side chain heteroatom and the receptor. Furthermore, the interaction of the C2 alkyl side chain with a hydrophobic pocket at the receptor binding site is suggested. In addition, NMR data in the companion paper indicate that the inactivity of the C8- substituted ATP analogues may be due to steric and conformational, rather than electronic, effects.