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. Ir is found that N-1 (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 t he active site of dihydrofolate reductase) to neutral and protonated 2 ,4-diamino triazine are also obtained. The highest binding energies ar e featured by the complex formed from a formate attached to the N-4 an d N-1 protonated forms of the triazine. However, as N-4 has a comparat ively low proton affinity (195.0 kcal/mol), it is unlikely that an int eraction of this nature would prevail. On the other hand, the formate- protonated N-1 interaction is similar to the structures identified by X-ray crystallography of enzyme-triazine complexes.