Binding free energy calculations of adenosine deaminase inhibitor and the effect of methyl substitution in inhibitors.

The binding affinity of an inhibitor is often improved ten times or more by introducing a simple substituent, such as a methyl group or a chlorine atom. We have investigated this phenomenon in the case of adenosine deaminase (ADA) inhibitors using molecular dynamics (MD) simulations and binding free energy calculations, by the linear interaction energy (LIE) method. For MD simulations, the coordination bond parameters and partial charges of atoms around the zinc ion in ADA have been determined by referring to ab initio MO calculations. The calculated binding free energies for seven inhibitors agreed well with the experimental ones, with a maximum error of 1.2 kcal/mol. The effect of methyl substitution in inhibitor molecules was examined on the basis of MD trajectories. It is suggested that the increase in binding affinity is caused by both van der Waals stabilizations by amino acid residues in contact with the introduced methyl group and through favored overall interactions with surrounding residues in the binding pocket.