Theoretical drug design: 6‐Azauridine‐5′‐phosphate—its X‐ray crystal structure, potential energy maps, and mechanism of inhibition of orotidine‐5′‐phosphate decarboxylase

The cytostatic drug 6‐azauridine is converted in vivo to 6‐azauridine‐5′‐phosphate (z6Urd‐5′‐P), which blocks the enzyme orotidine‐5′‐phosphate decarboxylase (Ord‐5′‐Pdecase) and therefore inhibits the de novo production of uridine‐5′‐phosphate (Urd‐5′‐P). In order to relate the structure and function of z6Urd‐5′‐P, it was crystallized as trihydrate, space group P212121 with a = 20.615 Å, b = 6.265 Å, c = 11.881 Å, and the structure established by Patterson methods. Atomic parameters were refined by full‐matrix least‐squares methods to R = 0.066 using 1638 counter measured x‐ray data. The ribose of z6Urd‐5′‐P is in a twisted C(2′)‐exo, C(3′)endo conformation, the heterocycle is in extreme anti position with angle N(6)‐N(1)‐C(1′)‐O(4′) at 86.3°, and the orientation about the C(4′)‐C(5′) bond is gauche, trans in contrast to gauche, gauche found for all the other 5′‐ribonucleotides. Conformational energy calculations show that z6Urd‐5′‐P may adopt an extreme anti conformation not allowed to Urd‐5′‐P, and they also predict the same unusual trans, gauche conformation about the C(4′)‐C(5′) bond in orotidine‐5′‐phosphate (Ord‐5′‐P) and in z6Urd‐5′‐P, which renders the distances O(2)…O(5′) in z6Urd‐5′‐P and O(7)…O(5′) in Ord‐5′‐P comparable. On this basis the function of z6Urd‐5′‐P as an Ord‐5′‐Pdecase inhibitor can be explained as being due to its structural similarity with the substrate Ord‐5′‐P and further clarifies the inhibitory action of 5′‐nucleotides bearing the heterocycles oxipurinol, xanthine, or allopurinol [J. A. Fyfe, R. L. Miller, and T. A. Krenitsky, J. Biol. Chem. 248, 3801 (1973)]. With this in mind, new inhibitors for Ord‐5′‐Pdecase may be designed.