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

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