The use of PM3 SCF MO quantum mechanical calculations to refine NMR-determined structures of complexes of antifolate drugs with dihydrofolate reductase in solution

Abstract PM3 SCF MO calculations were carried out on model compounds related to trimethoprim and an interacting aspartic acid in its binding site in the enzyme Lactobacillus casei dihydrofolate reductase. The systems examined included 2,4-diaminopyrimidine/acetic acid and trimethoprim/propionic acid. The calculations provided the geometric parameters describing the interaction of the trimethoprim N1 and 2-amino group protons with the carboxylate oxygen atoms of the conserved aspartic acid 26 residue in the enzyme. In the calculations where water molecules or protein fragments were included, the calculated ionisation states agreed with the experimentally observed results. Calculated structures obtained from docking trimethoprim with dihydrofolate reductase using constraints based on the results of the PM3 calculations together with the NMR-based distance constraints were compared with previous results obtained from calculations using only the NMR constraints.