Molecular recognition of modified adenine nucleotides by the P2Y(1)-receptor. 2. A computational approach

The molecular recognition of C2- or C8-substituted ATP derivatives by the P 2Y(1)-receptor (P2Y(1)-R) is analyzed using ab initio quantum mechanical ca lculations, Parameters that may determine ligand specificity toward P2Y(1)- 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 canno t explain the inactivity of the C8-substituted ATP derivatives, nor the dif ference in activity among the C2-substituted ATP analogues. These results i ndicate that neither tautomerism nor changes in the electronic distribution of the adenine ring play a major role in determining binding specificity o f adenine nucleotides to the receptor. It is suggested that the higher pote ncy of the CB-substituted ATP derivatives, compared to ATP, might be due to interaction between the C2 side chain heteroatom and the receptor. Further more, 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 com panion paper indicate that the inactivity of the C8-substituted ATP analogu es may be due to steric and conformational, rather than electronic, effects .