A CRYSTALLOGRAPHIC AND MOLECULAR MECHANICS STUDY OF INHIBITORS OF DIHYDROOROTASE

(1) Methyl L-dihydroorotate, C6HsN2O4, M(r) = 172.14, orthorhombic, P2(1)2(1)2(1), a = 6.941 (2), b = 9.708 (2), c = 23.329 (5) angstrom, V = 1572 angstrom3, Z = 8, D(x) = 1.455 g cm-3, Mo Kalpha, lambda = 0.71069 angstrom, mu = 0.81 cm-1, F(000) = 720, T = 294 K, final R = 0.036 for 793 reflections. (II) Methyl L-6-thiodihydroorotate, C6H8N2O3S, M(r) = 188.2 1, monoclinic, P2(1), a = 6.235 (2), b = 20.821 (4), c = 6.882 (1) angstrom, beta = 110.82 (2) , V = 835.0 angstrom3, Z = 4, D(x) = 1.497 g cm-3, MoKalpha, lambda = 0.71069 angstrom, mu = 3.02 cm-1, F(000) = 392, T = 294 K, final R = 0.037 for 1404 reflections. (III) Dimethyl trans-2-oxohexahydropyrimidine-4,6-dicarboxylate, C8Hl2N2O5, M(r) = 216.20, triclinic, P1BAR, a = 7,3977 (5), h = 8.4149 (8), c = 9.314 (1) angstrom, alpha = 74.65 (1), beta = 68.08 (1), gamma = 98.77 (1) , V = 502.80 angstrom, Z = 2, D(x) = 1.428 g cm-3, Mo Kalpha, lambda 0.71069 angstrom, mu = 0.78 cm-1, F(000) = 228, T = 294 K, final R = 0.040 for 1468 reflections. (IV) Dimethyl 2-oxo-1,2,3,6-tetrahydropyrimidine-4,6-di-carboxylate, C8H10N2O5, M(r) = 214.18, triclinic, P1BAR, a = 7.481 (3), b = 8.344 (3), c = 9.042 (5) angstrom, alpha = 95.05 (3), beta = 111.02 (3), gamma = 108.31 (3)-degrees, V = 487.18 angstrom3, Z = 2, D(x) = 1.460 g cm-3, Mo Kalpha, lambda = 0.71069 angstrom, mu = 0.78 cm-1, F(000) = 224, T = 294 K, final R = 0.040 for 1253 reflections. The three-dimensional structures of the methyl esters of dihydroorotate and three potential inhibitors of the enzyme, dihydroorotase, have been determined. Correlations between the structures of these compounds and their inhibitory activities are discussed. It is postulated that for strong binding to dihydroorotase to occur, a pyrimidine ring with three groups capable of forming strong interactions is required; two of these groups must be coplanar with the ring or equatorially disposed, and the third group must be axially disposed. Molecular mechanics modeling has been used to investigate the conformational iso-merism of the compounds and the role it plays in determining binding and consequent inhibition of dihydroorotase.