Computer graphic modeling in drug design--conformational analysis of antifolate binding to avian dihydrofolate reductase: crystal and molecular structures of 2,4-diamino-5-cyclohexyl-6-methylpyrimidine and 5-cyclohexyl-6-methyluracil.
The results of crystal structure determinations of the antifolate 2,4-diamino-5-cyclohexyl-6-methylprimidine (I), and its uracil derivative (II), show that the 5-cyclohexyl ring is gauche to the planar pyrimidine ring with torsion angles 82.4 (3) degrees and 63.7 (3) degrees for (I) and (II), respectively. Hydrogen bond patterns observed for these free base pyrimidines indicate a preference for N...N or N...O dimer formation around inversion centers, as observed in other antifolate structures. Computer graphic modeling studies were carried out comparing the avian dihydrofolate reductase active site interactions of the cyclohexyl antifolate (I) with the more potent 5-adamantyl analog and the less potent 5-hexyl and 5-heptyl antifolates. These data showed that although the cyclohexyl ring fits into the same conformational space as adamantyl, it makes fewer hydrophobic contacts. Similarly, cyclohexyl fills the active site better than either the 5-n-hexyl or heptyl side chains. These data are consistent with the increased potency of the adamantyl and cyclohexyl antifolates compared to n-alkyl analogs with similar hydrophobicities. These data indicate that the rigid structure of these ring systems increases their hydrophobic interactions, thus enhancing their biochemical activity.