Ab initio studies of 2,4-diamino triazine and its complexes with ligands: A model for inhibitor-active site interactions of dihydrofolate reductase

The protonation energies of 2,4-diamino triazine, an inhibitor of the therapeutic target dihydrofolate reductase, has been calculated using ab initio (Hartree-Fock) calculations. It is found that N₁ (see Fig. 1) exhibits the highest proton affinity (261.6 kcal/mol) by comparison with other inhibitor protonation sites. The energies of binding of the formate ion and formamide (as models for the amino acid residues in the active site of dihydrofolate reductase) to neutral and protonated 2,4-diamino triazine are also obtained. The highest binding energies are featured by the complex formed from a formate attached to the N₄ and N₁ protonated forms of the triazine. However, as N₄ has a comparatively low proton affinity (195.0 kcal/mol), it is unlikely that an interaction of this nature would prevail. On the other hand, the formate-protonated N₁ interaction is similar to the structures identified by X-ray crystallography of enzyme-triazine complexes.