Structure-Based Design of Inhibitors of Purine Nucleoside Phosphorylase. 4. A Study of Phosphate Mimics

Abstract

9-(3,3-Dimethyl-5-phosphonopentyl)guanine was synthesized and found to be a potent inhibitor of purine nucleoside phosphorylase (PNP) (IC50 = 44 nM). A number of other functional end groups were investigated as phosphate mimics attached to the 9-position of guanine by this same alkyl side chain, which provided a sensitive method for the detection of any interaction of these groups with the phosphate binding site of PNP. Both the sulfonic acid (compound 13) and the carboxylic acid (compound 15) end groups interact significantly with the phosphate binding site, but in different ways, as determined by X-ray crystallographic analysis of the complexes. The sulfonic acid of 13, which binds about one-fourth as tightly as the phosphonate 12, binds in the phosphate subsite much like the phosphonic acid. The carboxylic acid, the interaction of which is much weaker, turns away from the center of the phosphate binding site to form hydrogen bonds with Ser 200 and Met 219. Thus, the only phosphate mimics that bind like phosphate itself are themselves highly ionic, probably with limited ability to penetrate cell membranes.

Exploring the other side of biologically relevant chemical space: Insights into carboxylic, sulfonic and phosphonic acid bioisosteric relationships

“…More than once the mutual replacement of these acidic moieties has been exploited to develop bioisosteric series of biologically active compounds such as enzyme inhibitors (1-3) [22], receptor agonists (4,5,7,12) and antagonists (6,8,9) ( Fig. 1) [23][24][25][26][27].…”

“…For instance, carboxylic, sulfonic and phosphonic groups were used to functionalize the end group of alkyl chain attached to the nine position of guanine in order to synthesize inhibitors of purine nucleoside phosphorylase [22]. Results pinpointed that while phosphonate (3) and sulfonate (2) moieties interacted well with the binding site of the enzyme, the carboxylic group (1) did not yield a strong interaction.…”

The use of biodiversity as source of new chemical entities against defined molecular targets for treatment of malaria, tuberculosis, and T-cell mediated diseases: a review

“…Further crystallographic studies improved the resolution to 2.8 Å (Ealick et al 1991). These atomic coordinates were extensively used for structure-based design of PNP inhibitors (Woo et al 1992, Chern et al 1993, Guida et al 1994, Morris et al 2000. However, the deposited atomic coordinates of human PNP (PDB access codes: 1ULA and 1ULB) were recently withdrawn due to low resolution.…”

Identification of Novel Potent Inhibitors for ATP-Phosphoribosyl Transferase Using Three-Dimensional Structural Database Search Technique

“…These suggest that the simultaneous occupation of both substrate-binding sites enables PRibPP to have high affinity to the enzyme. This bi-substrate mimicking approach is reported in the study to design purine-nucleoside phosphorylase (PNP) inhibitor for the treatments of psoriasis and cultaneous T-cell lymphoma, which is one of the most famous and successful studies using the structure-based drug design technique [24][25][26][27][28]. PNP catalyzes the reversible conversion of purine nucleosides, (deoxy)guanosine or (deoxy)inosine, to the base and sugar-phosphate.…”