AM1 MOLECULAR-ORBITAL STUDIES OF THE STRUCTURES, CONFORMATIONS, PROTONATION ENERGIES, AND ELECTRONIC-PROPERTIES OF TRIAZINE DIHYDROFOLATE-REDUCTASE INHIBITORS

The structural, conformational, and electronic properties of three triazine antifolates were determined by AM1 molecular orbital calculations, and the results were compared with other theoretical studies and with X‐ray crystallographic studies of these and similar triazines both in the crystalline state and as complexes bound to dihydrofolate reductase. Calculated protonation energies confirm crystal structure data indicating N‐protonation analogous to that reported for MTX in similar environments. Overall, the calculated structural and conformational properties are in good agreement with X‐ray crystallographic results for these and similar triazines as found in the crystalline state and in enzymebound ternary complexes. However, for one triazine AM1 predicts a conformation with the bulky aromatic substituent twisted about 60° away from coplanarity with the triazine ring, in contrast to the nearly coplanar conformation found in the crystalline state. Intermolecular interactions favoring the coplanar conformation may thus be operative in the crystalline environment. The unique conformational preferences and greater conformation flexibility of triazines in general and of this triazine in particular may provide a key to understanding their biological activity. Copyright © 1990 John Wiley & Sons, Inc.